FIELD OF THE INVENTION

This invention relates to a new use of compounds that are angiotensin II (Ang II) agonists, more particularly selective agonists of the Ang II type 2 receptor (hereinafter the AT2 receptor), and especially agonists that bind selectively to that receptor, for prevention/reduction of risk/reduction of severity/reduction of the occurrence of cancer treatm e nt- re I ated ca rd i otoxi ci ty . BACKGROUND OF THE INVENTION

Over several decades, experimental and clinical research, as well as the development of new effective drugs, have resulted in an improved management of cancer patients, with subsequent reduced mortality and morbidity. The 14 million pediatric and adult cancer survivors living in the United States clearly demonstrate continued improvements in anti- cancer treatment efficacy. However, this success has been tempered by a parallel rise in the incidence of cancer treatment-related toxicity. Cancer treatment-related cardiotoxicity can occur as a consequence of direct effects on cardiac myocytes (function or protective mechanisms) and may include damage to the vascular endothelium, hemodynamic flow alterations and thrombotic events. Cardiotoxicity presents acutely during cancer treatment, potentially limiting dose and reducing the effectiveness of cancer treatment, and decades after treatment, leading to early mortality due to accelerated treatment-induced heart disease.

Anti-cancer treatments associated with cardiovascular risk include cytotoxic chemotherapies, targeted agents, immunomodulatory therapies and radiation, all of which have different anti-tumor mechanisms and on- and off-target effects that will influence what type of cardiac damage occurs. While mechanisms contributing to cardiotoxicity for selected agents have been proposed, few have been explored in the clinical setting for translation into effective prediction, prevention, detection and management methods for cancer treatment- related cardiotoxicity during cancer treatment and survivorship care. The discovery and increasing use of molecularly targeted cancer therapies, multi-modality treatments, and multidrug regimens for cancer treatment has widened this knowledge gap and changed the profile of cardiotoxicity in terms of timing and presentation. Current evidenced-based guidelines for preventing and controlling cancer treatment-related cardiotoxicity are broad, based on a nth racy dines and lack specific risk evaluation, prevention, monitoring, and management strategies for subgroups of patients. The patient population developing cancer treatment- related cardiovascular injury differs from those with primary cardiac dysfunction, requiring collaboration between oncologists, cardiologists and multidisciplinary team members to maximize cancer and cardiac outcomes.

A clinical trial evaluating the effects of candesartan as a preventive medication for cancer treatment-related cardiotoxicity, has recently been published (Gulati et al EHJ 2016). Candesartan is an Angiotensin II type 1 (AT1) receptor antagonist, which selectively binds to and blocks the AT1 receptor of the Renin-Angiotensin System, RAS. The study indicates that female patients with breast cancer receiving anthracycline-containing regimens concomitantly treated with candesartan will get a significant protective effect on cardiotoxicity caused by cancer treatment. However, this modest protective effect of candesartan demonstrates further needs of more effective therapies. SUMMARY OF THE INVENTION

Compounds of the invention are agonists of angiotensin II (Ang II), more particularly, are agonists of the AT2 receptor, and, especially, are selective agonists of that sub-receptor. In some embodiments, the compounds of the invention are those that can stimulate AT2 receptors.

Thus, in one aspect, a method is provided for preventing/reducing the risk of/reducing the occurrence of/ reducing the severity of cardiotoxicity associated with cancer treatment in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a composition comprising at least one angiotensin II receptor agonist, or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some aspects, the at least one angiotensin II receptor agonist can be a selective agonist of an angiotensin II type 2 (AT2) receptor. In other aspects, the at least one angiotensin II receptor agonist can be an angiotensin II type 2 (AT2) receptor agonist, and is preferably A/-butyloxycarbonyl-3-(4- imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamid e (C21), or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some aspects, the at least one angiotensin II receptor agonist may be administered with at least one other angiotensin II receptor agonist, at least one angiotensin II type 1 (AT1) receptor antagonist and/or at least one angiotensin converting enzyme (ACE) inhibitor.

The inventors have found that compounds that are angiotensin II receptor agonists, and more particularly agonists of the angiotensin II type 2 receptor (the AT2 receptor), and especially agonists that bind selectively to that receptor, are of use in the treatment and/or prevention/reduction of the risk of/reduction of the occurrence of/reduction of the severity of cancer treatment-related cardiotoxicity when the AT2 receptor agonist is administered to the subject in need. As described herein, compounds of the invention (e.g., AT2 receptor agonists or compounds that stimulate AT2 receptors), or pharmaceutically acceptable salts, solvates or prodrugs thereof can be used for prevention/reduction of the risk of/reduction of the occurrence of/reduction of the severity of cancer treatment-related cardiotoxicity. In some embodiments, a compound of the invention can be A/-butyloxycarbonyl-3-(4-imidazol-1- ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (Compound 21 or, in short, C21), or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Compounds of the invention may also be administered in combination with other AT2 agonists that are known in the art, as well as in combination with AT1 receptor antagonists that are known in the art, and/or in combination with an inhibitor of angiotensin converting enzyme (ACE).

In one embodiment of the present invention, there is provided a method for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity, which method comprises administration of a therapeutically effective amount of a compound of the invention (or a pharmaceutically acceptable salt, solvate or prodrug thereof) to a subject suffering from cancer. In a related embodiment, there is provided a method comprising administration of a therapeutically effective amount of a compound of the invention (or a pharmaceutically acceptable salt, solvate or prodrug thereof) to a subject suffering from cancer, before, during and/or after initiation of the cancer treatment.

In another embodiment of the invention, there is provided a composition comprising at least one angiotensin II receptor agonist (e.g. an angiotensin II type 2 (AT2) receptor agonist), and/or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, for use in preventing/reducing the risk of/reducing the occurrence of/ reducing the severity of cardiotoxicity associated with cancer treatment.

In another embodiment of the invention, compounds of the invention (e.g., AT2 receptor agonists or compounds that stimulate AT2 receptors), or pharmaceutically acceptable salts, solvates or prodrugs thereof, may also be used in the manufacture of a medicament for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity. In some embodiments, the compound can be A/-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-bu tylthiophene-2-sulfonamide (C21), or a pharmaceutically acceptable salt, solvate or prodrug thereof, which may be used in the manufacture of a medicament for the prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

According to a further embodiment of the invention, there is provided a method for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity, which method comprises administering a compound of the invention (e.g., an AT2 receptor agonist or other compound that stimulates an AT2 receptor, or a pharmaceutically acceptable salt, solvate or prodrug thereof) to a subject in need of such prevention/reduction of the risk/reduction of the occurrence/reduction of the severity. In some embodiments, a method for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity, comprises administering (e.g. a therapeutically effective amount of) the compound /V-butyloxycarbonyl- 3-(4-imidazol-1 -ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (C21 ), or a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject in need of such prevention therapy.

Other embodiments and advantages will be more fully apparent from the following disclosure.

DETAILED DESCRIPTION

The foregoing and other aspects of the present invention will now be described in more detail with respect to the description and methodologies provided herein. It should be appreciated that the invention may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

All patents, patent applications and publications referred to herein are incorporated by reference in their entirety for the teachings relevant to the sentence and/or paragraph in which the reference is presented. In the event of conflicting terminology, the present specification is controlling. Further, the embodiments described in one aspect of the present invention are not limited to the aspect described. The embodiments may also be applied to a different aspect of the invention as long as the embodiments do not prevent these aspects of the invention from operating for their intended purpose.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

Preferences and options for a given aspect, feature or parameter of the invention should, unless the context indicates otherwise, be regarded as having been disclosed in combination with any and all preferences and options for all other aspects, features and parameters of the invention. For example, the many of the aspects and features associated with a pharmaceutical formulation may equally apply to a compound of the invention, and vise versa.

The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the embodiments of the invention, the singular forms "a," "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items. Furthermore, the term "about," as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, refers to variations of 20%, 10%, 5%, 1 %, 0.5%, or even 0.1 % of the specified amount. When a range is employed (e.g., a range from x to y) it is it meant that the measurable value is a range from about x to about y, or any range or value therein including x and y, such as about xi to about yi , etc. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, components and/or groups, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

"Effective amount" as used herein refers to an amount of a compound, composition and/or formulation of the invention that is sufficient to produce a desired effect, which can be a therapeutic and/or beneficial effect. The effective amount will vary with the age, general condition of the subject, the severity of the condition being treated, the particular agent administered, the duration of the treatment, the nature of any concurrent treatment, the pharmaceutically acceptable carrier used, and like factors within the knowledge and expertise of those skilled in the art. As appropriate, an "effective amount" in any individual case can be determined by one skilled in the art by reference to the pertinent texts and literature and/or by using routine experimentation.

By the term "treat," "treating," or "treatment of" (and grammatical variations thereof) it is meant that the severity of the subject's condition is reduced, at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is achieved and/or there is a delay in the progression of the disease or disorder.

The terms "prevent," "preventing," and "prevention" (and grammatical variations thereof) refer to a delay in the extent or severity of a disease, disorder and/or clinical symptom(s) after onset relative to what would occur in the absence of carrying out the methods of the invention prior to the onset of the disease, disorder and/or clinical

symptom(s). The prevention can be complete, e.g., the total absence of the disease, condition and/or clinical symptom(s). The prevention can also be partial, such that the occurrence of the disease, disorder and/or clinical symptom(s) in the subject and/or the severity of onset is less than what would occur in the absence of the present invention.

Thus, the terms "prevent," "preventing," and "prevention" and like terms are used herein to include imparting any level of prevention or protection which is of some benefit to a subject, such that there is a reduction in the risk, the occurrence and/or the severity of the disease in a treated subject, regardless of whether the protection or reduction in incidence and/or severity is partial or complete. In some embodiments of the invention, preventing can mean reducing the risk of cardiotoxicity associated with cancer treatment.

A "therapeutically effective" amount as used herein is an amount that is sufficient to treat (as defined herein) the subject. Alternatively, a "therapeutically effective" amount as used herein is an amount that is sufficient to achieve the reduction or prevention specified herein. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.

A "subject" of the invention can include, but is not limited to, a mammalian subject. In some embodiments, the subject can be a human subject, a rodent subject (such as a mouse, a rat, or a hamster), or a domesticated animal subject (such as a dog, a cat, a pig, cattle, a sheep, a goat, a chicken, or a rabbit). In more particular embodiments, the subject is a human.

A "subject in need" of the methods of the invention can be a subject known to have or suspected of having cancer and at risk for treatment-related cardiotoxicity. Such subject in need is exemplified below, but not limited to:

(1) A patient with cancer who is going to be treated for, is being treated for, has been treated for the cancer.

(2) Patients with cancer and pre-existing cardiac dysfunction that are often excluded from effective cancer therapy because of increased risks for deterioration of heart function.

Using one or more compounds of the invention as a cardioprotective agent, with or without an AT1 receptor antagonist and/or an ACE inhibitor either before, during or after initiation of effective cancer therapy, the inclusion criteria for such therapy can be widened.

(3) A patient having a slight deterioration of heart function after initiation of effective cancer therapy. Such a condition often leads to reduced doses of the cancer therapy and possibly less effective cancer treatment. Concomitant treatment with a compound of the invention, with or without an AT1 receptor antagonist and/or an ACE inhibitor, may allow effective cancer therapy doses to be kept unchanged in many cancer patients.

(4) A patient undergoing radiation therapy to treat cancer. Radiation therapy is frequently used to treat certain patients with cancers of the lung, of the esophagus or of the breast. Such therapy is sometimes combined with cytostatic agents. If the tumors are located close to the heart, the risk for cardiotoxic radiation effects increases, and may result in enhanced formation of fibrosis in the myocardium or in the valves, leading to decreased cardiac function. By treatment with a compound of the invention, the risk for chronic radiation damage to the heart may be reduced.

The term "concomitant administration" or "combination administration" of a compound, therapeutic agent or known drug with a compound of the present invention means administration of a known medication or drug and, in addition, the one or more compounds of the invention to the same subject at such time that both the known drug and the compound will have a therapeutic effect. In some cases this therapeutic effect will be synergistic. Such concomitant administration can involve concurrent (i.e., at the same time), prior, or subsequent administration of the known drug with respect to the administration of a compound of the present invention. A person skilled in the art, would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compounds of the present invention.

In addition, in some embodiments, the compounds of this invention will be used, either alone or in combination with each other or in combination with one or more other therapeutic medications as described herein, or their pharmaceutically acceptable salts, solvates or prodrugs, for manufacturing a medicament for the purpose of providing for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

In a particular embodiment, other therapeutic medications include: an angiotensin II type 1 (AT1) receptor antagonist (such as candesartan); or an inhibitor of angiotensin converting enzyme (ACE).

Without wishing to be bound by theory, it is thought that renin, a protease, cleaves its only known substrate (angiotensinogen) to form angiotensin I, which in turn serves as substrate for angiotensin converting enzyme (ACE) to form Ang II. The endogenous hormone Ang II is a linear octapeptide (Asp ¹ -Arg ² -Val ³ -Tyr ⁴ -lle ⁵ -His ⁶ -Pro ⁷ -Phe ⁸ ), and is an active component of the renin-angiotensin system (RAS).

The angiotensin II type 1 (AT1) receptor is expressed in most organs, and is believed to be responsible for the majority of the pathological effects of Ang II.

Several studies in adult individuals appear to demonstrate that, in the modulation of the response following Ang II stimulation, activation of the AT2 receptor has opposing effects to those mediated by the AT1 receptor.

The AT2 receptor has also been shown to be involved in apoptosis and inhibition of cell proliferation (de Gasparo M et al. Pharmacol Rev 2000; 52:415-472).

More recently, AT2 receptor agonists have been shown to be of potential utility in the treatment and/or prophylaxis of disorders of the alimentary tract, such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see international patent application WO 99/43339).

The expected pharmacological effects of agonism of the AT2 receptor are described in general in de Gasparo M et al., Pharmacol Rev 2000; 52:415-472. However, it is not mentioned that agonism of the AT2 receptor may be used for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

The effects of Ang II on cell growth, inflammation and extracellular matrix synthesis are mainly coupled to AT1 , whereas the function of AT2 has been heavily investigated and new research indicates that it is more prevalent in damaged tissue and exerts reparative properties and properties opposing the AT1 receptor. The AT2 receptor has been shown to be important in reducing myocyte hypertrophy and fibrosis.

AT2 receptor agonists have also been described, for instance, in international patent application WO 2002/096883. However, these compounds were not suggested for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity. No clinical trials have so far been initiated with an agonist of the AT2 receptor to evaluate possible cardioprotective effects in patients diagnosed with cancer and subjected to cancer therapies.

Several known compounds or drugs may cause cardiotoxicity or have cardiotoxic effects (Florescu M. et al., Maedica (Buchar). 2013 Mar; 8(1): 59-6, Cardinale D., Circulation. 2006 Dec 5; 1 14 (23):2474-81). Anthracyclines may have the cardiovascular manifestations of LVD (left ventricular dysfunction), HF (heart failure), myocarditis, or arrhythmia. 5- Fluorourcil may have the cardiovascular manifestations of ischemia, HF, pericarditis, or cardiogenic shock. Taxanes (e.g. paclitaxel), and vinca alkaloids may have the cardiovascular manifestations of Sinus bradicardia, ventricular tachycardia, atrioventricular block, HF, or ischemia. Cyclophoshamide may have the cardiovascular manifestations of HF (neurohumoral activation), or mitral regurgitation. Trastuzumab may have the cardiovascular manifestations of HF, LVD, or arrhythmia. Tamoxifen may have the cardiovascular manifestations of thromboembolism, or cholesterol metabolism anomalies. Bevacizumab may have the cardiovascular manifestations of hypertension, or thromboembolism. COX-2 specific inhibitors may have the cardiovascular manifestations of thromboembolism. Further manifestations may for example include diastolic dysfunction and valvular insufficiency.

Thus, in some embodiments, the cancer treatment-related cardiotoxicity includes one or more symptoms selected from the group consisting of LVD (left ventricular dysfunction), HF (heart failure), myocarditis, arrhythmia, ischemia, pericarditis, cardiogenic shock, Sinus bradicardia, ventricular tachycardia, atrioventricular block, mitral regurgitation, thromboembolism, cholesterol metabolism anomalies, hypertension, diastolic dysfunction and valvular insufficiency. In preferred embodiments, the cancer treatment-related cardiotoxicity is LVD or heart failure.

Accordingly, in a first aspect of the invention, there is provided an AT2 receptor agonist (or a compound that stimulates AT2 receptors) or a pharmaceutically acceptable salt (preferably an HCI salt of a compound of the invention), solvate or prodrug thereof, for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity. As described herein, such AT2 receptor agonists and/or compounds that stimulate AT2 receptors may be referred to herein as the "compounds of the invention". In some embodiments, a compound of the invention can include, but is not limited to, A/-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso- butylthiophene-2-sulfonamide (C21), or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The skilled person will understand that references to an AT2 receptor agonist include references to compounds that can bind to the AT2 receptor and induce a biological response from the AT2 receptor.

Thus, a compound of the invention includes AT2 receptor agonists that fully activate and those that partially activate the AT2 receptor and those compounds that can stimulate or activate the AT2 receptor.

In some embodiments, an AT2 receptor agonist may be defined to include any compound that can stimulate or activate the AT2 receptor. In some embodiments, the compound of the invention is an AT2 receptor specific agonist that binds selectively to the AT2 receptor.

Particular compounds of the invention include A/-butyloxycarbonyl-3-(4-imidazol-1- ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (C21), or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Particular compounds of the invention that bind selectively to the AT2 receptor include

A/-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso -butylthiophene-2-sulfonamide (C21).

The structure of A/-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso- butylthiophene-2-sulfonamide (C21) is shown in Structure 1 , below.

According to a second aspect of the invention, there is provided the use of a compound of the invention, for example, the compound A/-butyloxycarbonyl-3-(4-imidazol-1- ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (C21) or a pharmaceutically acceptable salt (preferably an HCI salt of a compound of the invention), solvate or prodrug thereof, for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity. In another aspect of the invention, the compounds of the invention (e.g., AT2 receptor agonists, and other compounds that stimulate AT2 receptors), or pharmaceutically acceptable salts (e.g., an HCI salt of the compound of the invention), solvates or prodrugs thereof, may also be used in the manufacture of a medicament for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

According to a third aspect of the invention, there is provided a method for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity of which method comprises administering a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject in need of such treatment. In some embodiments, the compound of the invention can be A/-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-bu tylthiophene-2- sulfonamide (C21), or a pharmaceutically acceptable salt solvate or prodrug thereof. As described herein, a particular pharmaceutically acceptable salt of a compound useful in the methods of the invention that may be mentioned includes, but is not limited to, the HCI salt. A further particular pharmaceutically acceptable salt of a compound useful in the methods of the invention that may be mentioned includes the sodium salt.

Pharmaceutically-acceptable salts include, but are not limited to, acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo or by freeze-drying). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example, using a suitable ion exchange resin. For the avoidance of doubt, other pharmaceutically acceptable derivatives of compounds of the invention are included within the scope of the invention (e.g. solvates, prodrugs etc). Examples of pharmaceutically acceptable addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and arylsulphonic acids; and from metals such as sodium, magnesium, potassium and calcium. In representative embodiments, a pharmaceutically acceptable salt can be a hydrochloric acid salt.

As used herein, a "prodrug" is a composition that undergoes an in vivo modification when administered to a subject, wherein the product of the in vivo modification is a therapeutically effective compound. Prodrugs of compounds may be prepared by, for example, preparing a given compound as an ester. Thus, for example, an esterified form of the compound may be administered to a subject and may be de-esterified in vivo thereby releasing a therapeutically effective compound. Alternatively, some compounds may be prepared as prodrugs by adding short polypeptides (e.g. , 1-6 amino acids) to the compound. Such prodrugs when administered to a subject may be cleaved (by, e.g., trypsin or other peptidases/proteases) thereby releasing a therapeutically effective compound. Formation of prodrugs is not limited by the specific examples described herein. Other ways of preparing therapeutically effective compounds as prodrugs are known.

Compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

Compounds of the invention also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively, the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention. The compound A/-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso- butylthiophene-2-sulfonamide (C21) with the structure provided in Structure 1 , may be made in accordance with techniques well known to those skilled in the art, for example as described in international patent application WO 2002/096883, all of its content hereby incorporated by reference. In the case of a discrepancy between the name of the compound and the structure provided in Structure 1 , the structure provided in Structure 1 should prevail.

The compounds of the invention are useful because they possess pharmacological activity. In particular, the compounds of the invention are agonists of Ang II, more particularly, they are agonists of the AT2 receptor, and, especially, are selective agonists of that sub- receptor. Compounds of the invention have the advantage that they bind selectively to, and exhibit agonist activity at, the AT2 receptor. By compounds that "bind selectively" to the AT2 receptor, we include that the affinity ratio for the relevant compound (AT2:AT1) is at least 50: 1 , at least 100: 1 , preferably at least 1000: 1 , more preferably at least 10000: 1 , and even more preferably at least 25000: 1.

The present inventors have found that the compounds of the invention (e.g., AT2 receptor agonists) are useful for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity. According to a further aspect of the present invention, there is provided a method for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity, which method comprises administration of a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt (e.g, an HCI salt of a compound of the invention), solvate or prodrug thereof to a subject suffering from, such a condition.

In one embodiment, the compound of the invention may be used in a method of preventing cancer treatment-related cardiotoxicity. In another embodiment, the compound of the invention may be used in a method of reducing the risk of cancer treatment-related cardiotoxicity. In a further embodiment, the compound of the invention may be used in a method of reducing the occurrence of cancer treatment-related cardiotoxicity. In a yet further embodiment, the compound of the invention may be used in a method of reducing the severity of cancer treatment-related cardiotoxicity. Cancer treatment-related cardiotoxicity includes one or more symptoms as are hereinbefore described. In preferred embodiments, the cancer treatment-related cardiotoxicity is LVD or heart failure.

Cancer treatment-related cardiotoxicity includes any cardiotoxicity associated with the treatment of cancer resulting from or associated with the use of a known anti-cancer therapy, such as therapy using anthracyclines (e.g. doxorubicin), 5-fluorourcil, taxanes (e.g. paclitaxel), vinca alkaloids, cyclophosphamide, trastuzumab, tamoxifen, bevacizumab, or COX-2 specific inhibitors. In preferred embodiments, the cancer treatment-related cardiotoxicity is a cardiotoxicity resulting from or associated with treatment using an anthracycline, particularly doxorubicin.

In a particular embodiment, the compound of the invention (e.g. C21) may be used in a method of preventing or reducing the severity of LVD or heart failure in a patient who has been treated, is being treated or will be treated for cancer using an anthracycline-based therapy, such as doxorubicin.

The compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form. Additional methods of administration include but are not limited to intraarterial administration, intramuscular administration, intraperitoneal administration, intraportal administration, intradermal administration, epidural administration, and/or intrathecal administration.

The compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets (e.g. tablets for oral administration), capsules (e.g. capsules for oral administration), elixirs (e.g. elixirs for oral administration), suppositories (e.g. suppositories for rectal administration), sterile solutions (e.g. sterile solutions for parenteral administration or sterile solutions for intramuscular administration), or sterile suspensions (e.g. sterile suspensions for parenteral administration or sterile suspensions intramuscular administration), and the like. Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the molecule with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross- linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

According to a further aspect of the invention there is thus provided a pharmaceutical formulation comprising a compound of the invention, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

Acceptable carriers and diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro ed. 1985). The choice of pharmaceutical carriers and diluents can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical formulations may comprise as, or in addition to, the carriers and diluents any suitable binder, lubricant, suspending agent, coating agent, or solubilising agent. Preservatives, stabilisers, dyes and even flavouring agents may be provided in the pharmaceutical formulation.

Compounds of the invention may also be administered in combination with other AT2 agonists that are known in the art, as well as in combination with AT1 receptor antagonists that are known in the art, such as losartan or candesartan, and/or in combination with an inhibitor of angiotensin converting enzyme (ACE), such as enalapril or ramipril Such combinations may therefore be useful for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity in the therapeutic. Non-limiting but illustrative examples of AT1 receptor antagonists that can be used according to the embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, pratosartan, ripiasartan, saprisartan, tasosartan, telmisartan, valsartan and/or combinations thereof. Non-limiting but illustrative examples of ACE inhibitors that can be used according to the embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, alacepril, ceronapril, delepril, moveltipril, and/or combinations thereof.

According to another aspect of the invention, there is provided the use of at least one angiotensin II receptor agonist, and/or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, and at least one angiotensin II type 1 (AT1) receptor antagonist in the manufacture of a medicament for preventing/reducing the risk of/reducing the occurrence of/ reducing the severity of cardiotoxicity associated with cancer treatment.

There is also provided:

(i) a composition comprising at least one angiotensin II type 1 (AT1) receptor antagonist for use in preventing/reducing the risk of/reducing the occurrence of/ reducing the severity of cardiotoxicity associated with cancer treatment, wherein the at least one angiotensin II type 1 (AT1) receptor antagonist is administered in combination with at least one angiotensin II receptor agonist, and/or a pharmaceutically acceptable salt, solvate and/or prodrug thereof; and

(ii) the use of at least one angiotensin II type 1 (AT1) receptor antagonist in the manufacture of a medicament for preventing/reducing the risk of/reducing the occurrence of/ reducing the severity of cardiotoxicity associated with cancer treatment, wherein the medicament is administered either concomitantly or sequentially with at least one angiotensin II receptor agonist, and/or a pharmaceutically acceptable salt, solvate and/or prodrug thereof. According to a yet another aspect of the invention, there is provided the use of at least one angiotensin II receptor agonist, and/or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, and at least one inhibitor of angiotensin converting enzyme (ACE) in the manufacture of a medicament for preventing/reducing the risk of/reducing the occurrence of/ reducing the severity of cardiotoxicity associated with cancer treatment.

There is also provided:

(i) a composition comprising at least one inhibitor of angiotensin converting enzyme (ACE) for use in preventing/reducing the risk of/reducing the occurrence of/ reducing the severity of cardiotoxicity associated with cancer treatment, wherein the at least one inhibitor of angiotensin converting enzyme (ACE) is administered in combination with at least one angiotensin II receptor agonist, and/or a pharmaceutically acceptable salt, solvate and/or prodrug thereof; and

(ii) the use of at least one inhibitor of angiotensin converting enzyme (ACE) in the manufacture of a medicament for preventing/reducing the risk of/reducing the occurrence of/ reducing the severity of cardiotoxicity associated with cancer treatment, wherein the medicament is administered either concomitantly or sequentially with at least one angiotensin II receptor agonist, and/or a pharmaceutically acceptable salt, solvate and/or prodrug thereof.

In a particular embodiment of each aspect of the invention, the angiotensin II receptor agonist is preferably an angiotensin II type 2 (AT2) receptor agonist.

According to a further aspect of the invention, there is provided a combination product comprising:

(A) an AT2 receptor agonist and/or a compound that stimulates AT2 receptors, and · (B) an AT1 receptor antagonist, and/or an ACE inhibitor,

wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically- acceptable adjuvant, diluent or carrier, for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity. Such combination products provide for the administration of an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor (as defined herein), in conjunction with an AT1 receptor antagonist and/or an ACE inhibitor, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises an AT2 receptor agonist or a compound that stimulates an AT2 receptor (as defined herein, e.g., a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof), and at least one formulation comprises an AT1 receptor antagonist and/or an ACE inhibitor, or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation including an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor together with either an AT1 receptor antagonist or an ACE inhibitor (or both)).

Thus, there is further provided:

(1) a pharmaceutical formulation comprising an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor (e.g., a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof) and an AT1 receptor antagonist or an ACE inhibitor in admixture with a pharmaceutically-acceptable adjuvant, diluent and/or carrier, for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity; and

(2) a kit of parts comprising components:

(a) a pharmaceutical formulation comprising an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor (e.g., a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof), in admixture with a pharmaceutically-acceptable adjuvant, diluent and/or carrier; and

(b) a pharmaceutical formulation including an AT1 receptor antagonist, or an ACE inhibitor, in admixture with a pharmaceutically-acceptable adjuvant, diluent and/or carrier,

which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other, for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity. Depending upon the subject to be treated and the route of administration, the compounds of the invention may be administered at varying doses. Although doses will vary from subject to subject, suitable daily doses are in the range of about 1 to 1000 mg (e.g., about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, 100, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg, and the like, or any range or value therein) per subject, administered in single or multiple doses. More preferred daily doses are in the range 2.5 to 250 mg (e.g., about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg and the like or any range or value therein) per subject.

Individual doses of compounds of the invention may be in the range 1 to 100 mg (e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg , about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85mg, about 90 mg, about 95 mg, or about 100 mg, and the like, or any range or values therein). Advantageously, compounds of the present invention may be administered in single doses, e.g. once daily or more seldom, or in a total daily dosage administered in divided doses of two, three or four times daily. In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual subject, which is likely to vary with the condition that is to be treated, as well as the age, weight, sex and response of the particular subject to be treated. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

In a particular embodiment, the compounds of the present invention may be administered over a period of at least two days; for example, at least three days, or at least four days, or at least five days, or at least six days, or at least seven days (i.e. one week), or at least eight days, or at least nine days, or at least ten days, or at least 1 1 days, or at least 12 days, or at least 13 days, or at least 14 days (i.e. two weeks), or at least three weeks, or at least four weeks, or at least one month, or at least five weeks, or at least six weeks, or at least seven weeks, or at least eight weeks, or at least two months, or at least three months, or at least four months, or at least five months, or at least six months, or at least seven months, or at least eight months, or at least nine months, or at least ten months, or at least

1 1 months, or at least 12 months (i.e. one year), or at least two years, or at least three years, or at least four years, or at least five years, or at least six years, or at least seven years, or at least eight years, or at least nine years, or at least ten years, or at least 11 years, or at least

12 years, or at least 13 years, or at least 14 years, or at least 15 years, or at least 16 years, or at least 17 years, or at least 18 years, or at least 19 years, or at least 20 years, or at least

25 years, or at least 30 years, or at least 35 years, or at least 40 years, or at least 45 years, or at least 50 years.

The compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties than compounds known in the prior art. Such effects may be evaluated clinically, objectively and/or subjectively by a health care professional, a treatment subject or an observer.

Accordingly, in some embodiments, a method for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity of in a subject in need thereof is provided, comprising: administering to said subject a therapeutically effective amount of an angiotensin II (AT2) receptor agonist and/or a pharmaceutically acceptable salt, solvate, solvate of a pharmaceutically acceptable salt, or prodrug thereof, thereby for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity in said subject. In some embodiments, the AT2 receptor agonist is an AT2 specific agonist. In some embodiments, the AT2 receptor agonist is A/-butyloxycarbonyl-3-(4-imidazol-1- ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (C21) or a pharmaceutically acceptable salt, solvate, solvate of pharmaceutically acceptable salt, or prodrug thereof. In some embodiments, the AT2 receptor agonist is the compound depicted in Structure 1.

In some embodiments, the method comprises administering to said subject a therapeutically effective amount of an AT1 receptor antagonist and/or an angiotensin converting enzyme (ACE) inhibitor. In some embodiments, the AT2 receptor agonist is provided in the same composition or pharmaceutical formulation as the AT1 receptor antagonist and/or the ACE inhibitor. In some embodiments, AT2 receptor agonist is provided in a different formulation from the AT1 receptor antagonist and/or the ACE inhibitor and the separate formulations are administered to the subject simultaneously, sequentially or separately. In some embodiments, the composition or pharmaceutical formulation comprises a pharmaceutically-acceptable adjuvant, diluent and/or carrier. In some embodiments, administering comprises oral administration, intravenous administration, subcutaneous administration, buccal administration, rectal administration, dermal administration, nasal administration, tracheal administration, bronchial administration, inhalation administration, intraarterial administration, intramuscular administration, intraperitoneal administration, intraportal administration, intradermal administration, epidural administration, and/or intrathecal administration. In some embodiments, the present invention provides a kit for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity, comprising a pharmaceutical formulation comprising AT2 receptor agonist. In some embodiments, the kit further comprises a pharmaceutical formulation comprising an AT1 receptor antagonist and/or an ACE inhibitor. In some embodiments, the kit further comprises instructions for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity for with an effective amount of the pharmaceutical formulation. In some embodiments, the kit further comprises an AT2 receptor agonist that is the AT2 receptor agonist depicted in Structure 1.

In some embodiments, a compound for use for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity is provided, wherein the compound is an AT2 receptor agonist, or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the use of a compound in the manufacture of a medicament for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity is provided, wherein the compound is an AT2 receptor agonist, or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, a method for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity is provided, comprising the administration of a compound which is an AT2 receptor agonist, or a pharmaceutically acceptable salt, solvate or prodrug thereof, to a patient in need of such therapy. In some embodiments, the compound is a compound which is capable of stimulating AT2 receptors. In some embodiments, the compound is a compound that binds selectively to the AT2 receptor. In some embodiments, the compound is A/-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5- / ^' so-butylthiophene-2-sulfonamide.

In some embodiments, a pharmaceutical formulation is provided comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

In some embodiments, a pharmaceutical formulation is provided comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and an AT1 receptor antagonist, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

In some embodiments, a kit of parts is provided comprising components:

(a) a pharmaceutical formulation including a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including an AT1 receptor antagonist, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,

which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other, for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

In some embodiments, a pharmaceutical formulation is provided including a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and an angiotensin converting enzyme inhibitor, in admixture with a pharmaceutically- acceptable adjuvant, diluent or carrier, for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

In some embodiments, a kit of parts is provided comprising components:

(a) a pharmaceutical formulation including a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including an angiotensin converting enzyme inhibitor, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other, for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

In some embodiments, the present invention provides an AT2 receptor agonist as described herein, an AT2 receptor agonist for use as described herein, pharmaceutical formulation as described herein, pharmaceutical formulation for use as described herein, a use as described herein, a method as described herein, a compound as described herein, a compound for use as described herein, a combination product as described herein, a combination product for use as described herein, a kit-of-parts as described herein, a kit-of- parts for use as described herein for prevention/reduction of the risk/reduction of the occurrence/reduction of the severity of cancer treatment-related cardiotoxicity.

The invention will now be described with reference to the following examples. It should be appreciated that these examples are not intended to limit the scope of the claims to the invention, but are rather intended to be exemplary of certain embodiments. Any variations in the exemplified methods that occur to the skilled artisan are intended to fall within the scope of the invention.

EXAMPLES

Example 1 : The effect of angiotensin li type 2 receptor agonist C21 , with or without combination with losartan, on doxorubicin induced heart failure Aim: In heart failure, most deleterious effects of the renin-angiotensin system on the cardiovascular system are mediated by angiotensin (AT) II type 1 -receptors. However, ATI I type 2-receptors have a capability to compensate or antagonize these deleterious effects. Up to now, the effects of an ATI I type 2-receptor agonist in heart failure, induced by the cancer- medication doxorubicin (DOX), has not been studied. To test the potential beneficial effects, a study was performed to evaluate the ATI I type 2-receptor agonist C21 with or without combination with losartan on DOX-induced heart failure in rat hearts in vivo.

Methods: Rats were randomized into five groups (n = 8); (1) control group, (2) a DOX group (a single dose of 20mg/kg), (3) a DOX + C21 group, (0.3mg/kg for 21 days), (4) a DOX + losartan group (20mg/kg losartan for 21 days) and (5) a DOX + losartan ÷ C21 group (0.3mg/kg C21 and 20mg/kg losartan for 21 days). Histological and echocardiographic examinations of rat hearts were done to define the effects of study drugs.

Results: Left ventricular (LV) systolic function was examined by transthoracic echocardiography both at the beginning and at the end. Only DOX administered group showed reduced left ventricle ejection fraction compared to other study groups and before DOX administration (p=0.009, p<0.005). There was no difference on LV function between the DOX + C21 group, DOX + losartan group and DOX + losartan + C21 groups (Tabiel).

Table 1. Systolic function

LVESD (mm) 2.6 ± .7 3.0 ±1.1 ^& 2.4 ± .5 2.6 ± .52 3.1 ± .78 before

LVESD (mm) 3.4±.9 3.9 ±1.2 ^& 3.0± .75 3.4 ± .52 2.9 ± .6 after

LV EF (%) before 79.5 ± 8.3 80.8 ± 4.8 ^& 83.1 ± 5.6 81.2 ± 3.2 79.1 ± 9.7

LV EF (%) after 73.6± 57.2 ± 73.5±8.5 73.5 ± 6.6 71.1 ± 12.7

12.4 _{13 7} * &

Heart rate before 231 ± 282 ± 79.6 278 ± 58.4 245 .2 ± 275± 54.5 (beats per 48.8

minute) 22.7

Heart rate after 269 ± 281 ± 79.6 225.7 ± 23.8 241 ± 60.7 289 ± 78.3 (beats per 67.8

minute)

*p=0.009 between all study grups, ^& p<0.005 for before and after measurements only in doxorubicine administration group. LVED: Left ventricle enddiastolic volume, LVES: Left ventricle endsystolic volume, LV EF: Left ventricle ejection fraction.

Direct microscopic examination revealed reduced DOX toxicity in both losartan and C21 groups. The DOX + losartan ÷ C21 group showed reduced overall toxicity compared to DOX + losartan or DOX + C21 groups (Table 2).

Similar differences between groups were seen regarding myocyte apoptosis (staining with caspase 3).

Table 2. Effects of preventive treatment on histological alterations in myocardium of DOX applied rats.

Data presented as median (min-max)

a Statistically significant increase when compared with control group (P <0.05), ^b Statistically significant decrease when compared with DOX group (P <0.05),

c Statistically significant increase when compared with DOX + C21 group (P <0.05),

d Statistically significant decrease when compared with DOX + los group (P <0.05),

e Not significant when compared with DOX + C21 (P>0.05).

f Statistically significant decrease when compared with DOX + los and DOX + C21 groups (P <0.05),

Conclusions: The AT II type 2-receptor agonist C21 attenuates the deleterious effects of the renin-angiotensin system on heart failure, to an extent similar to the AT II type-1 receptor antagonist losartan, and the most pronounced protective effect was seen after a combination of the two drugs. Taken together, preventive treatment with C21 , alone or in combination with a AT1 receptor antagonist (such as losartan) represents a novel approach for patients to prevent cardiotoxicity induced by the cancer-medication doxorubicin.

The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.