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Title:
CHEMOTHERAPEUTICALLY ACTIVE SACCHARIDE
Document Type and Number:
WIPO Patent Application WO/2018/031435
Kind Code:
A1
Abstract:
Herein are described chemotherapeutically active compositions that include a thermally activated saccharide. The thermally active saccharide (a chemotherapeutically active saccharide) can be selected from a thermally activated maltodextrin, a thermally activated fructose, and/or a thermally activated inulin. These thermally activated saccharides are further described in admixtures with carries (e.g., pharmaceutically-acceptable carriers), additional adjuvants, diluents, binders, and the like. Still further, a method of treating a subject with the chemotherapeutically active saccharides is disclosed and can include (a) identifying the subject presenting symptoms of cancer; (b) administering an effective amount the chemotherapeutically active composition (e.g., saccharide); and, optionally (c) simultaneously, sequentially, or separately administering to the subject an effective amount a different chemotherapeutic agent.

Inventors:
SHIMOMURA KAZUHIRO (US)
OUCHI TORU (US)
Application Number:
PCT/US2017/045673
Publication Date:
February 15, 2018
Filing Date:
August 07, 2017
Export Citation:
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Assignee:
RMD SCIENCES INC (US)
International Classes:
A61P35/02; C07D307/48; C07D307/50
Other References:
ROSATELLA, AA ET AL.: "5- Hydroxymethylfurfural (HMF) as a building block platform: Biological properties, synthesis and synthetic applications", GREEN CHEMISTRY, vol. 13, 2011, pages 754 - 793, XP002714416
MORALES, FJ ET AL.: "Antioxidant activity of cookies and its relationship with heat-processing contaminants: a risk/benefit approach.", EUROPEAN FOOD RESEARCH AND TECHNOLOGY, vol. 228, 2009, pages 345 - 354, XP019653072
Attorney, Agent or Firm:
GOODMAN, Jonathan (US)
Download PDF:
Claims:
WHAT IS CLAIMED:

1. A chemotherapeutically active composition comprising a thermally activated saccharide selected from a thermally activated maltodextrin, a thermally activated fructose, and/or a thermally activated inulin.

2. The chemotherapeutically active composition of claim 1 , wherein the maltodextrin is selected from the group consisting of maltose, maltotriose, maltotetraose, maltopentaose, maltohexose, a product from an amylase mediated digestion of a starch, and a mixture thereof; preferably, wherein the maltodextrin is selected from the group consisting of maltose, maltotriose, and a mixture thereof.

3. The chemotherapeutically active composition of any one of the preceding claims, wherein the thermally activated saccharide consists of the thermally activated maltodextrin.

4. The chemotherapeutically active composition of claim 1 , wherein the thermally activated saccharide consists of the thermally activated fructose.

5. The chemotherapeutically active composition of claim 1 , wherein the thermally activated saccharide consists of the thermally activated inulin.

6. The chemotherapeutically active composition of claim 1 , wherein the thermally activated saccharide consists of a plurality of the thermally activated maltodextrin, thermally activated fructose, and thermally activated inulin.

7. The chemotherapeutically active composition of any one of the preceding claims, wherein the thermally activated maltodextrin, thermally activated fructose, and thermally activated inulin are, respectfully, products from the thermal activation of maltodextrin, fructose, and inulin.

8. The chemotherapeutically active composition of any one of the preceding claims, wherein the thermally activated saccharide has a molecular weight of about 324, 342, 486, and/or 504 daltons.

9. The chemotherapeutically active composition of any one of the preceding claims, wherein the thermally activated saccharide is mono-dehydrated; preferably, having a molecular weight selected from 324 and 486 daltons.

10. The chemotherapeutically active composition of any one of the preceding claims, wherein the thermally activated saccharide provides an HCT 1 16 Cell Death of at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%.

11. The chemotherapeutically active composition of any one of the preceding claims, wherein the thermally activated saccharide provides a Normal Cell Death of less than 25%, less than 20%, less than 15 %, less than 10%, or less than 5%; preferably, the Normal Cell Death is indistinguishable from a control that did not include the thermally activated saccharide.

12. A chemotherapeutically active composition comprising a thermally activated saccharide obtainable by exposing a maltodextrin, fructose, and/or inulin to a heat source until it is thermally activated.

13. The chemotherapeutically active composition of claim 12, wherein the thermally activated saccharide is obtainable by exposing maltodextrin, fructose, and/or inulin to a dry heat source; wherein the heat source is between about 1 10 °C and about 210 °C; preferably between about 120 °C and about 120 °C, 130 °C, 140 °C, 150 °C, 160 °C, 170 °C, or about 180 °C.

14. A composition comprising:

the chemotherapeutically active composition of any one of claims 1-13 and a pharmaceutically-acceptable carrier.

15. A method of treating a subject comprising:

(a) identifying the subject presenting symptoms of cancer wherein said symptoms warrant treatment with a chemotherapeutic agent;

(b) administering an effective amount the chemotherapeutically active

composition of any of claims 1-13; and, optionally

(c) simultaneously, sequentially, or separately administering to the subject an effective amount a chemotherapeutic agent.

16. The method of claim 15, wherein during the identification step (a) it is determined that at least one of the chemotherapeutic agent listed in Table 1 would be beneficial for the treatment of the subject.

17. The method of any one of claims 15-16, wherein the subject's symptoms of cancer have been shown to more effectively reduced by treatment with the chemotherapeutic agent of step (c) and the chemotherapeutically active composition than by the chemotherapeutic agent of step (c) alone in a controlled study comparing the effectiveness of the

chemotherapeutic agent of step (c) and the effectiveness of chemotherapeutic agent of step (c) and the chemotherapeutically active composition.

18. The method of any one of claims 15-17, wherein the chemotherapeutically active composition is administered topically.

19. The method of any one of claims 15-18, wherein the cancer of step (a) is further diagnosed as a carcinoma; a sarcoma; a melanoma; a lymphoma; a leukemia; a brain tumor; a cancer found in the blood; a cancer found in a tissue in the skin; a cancer found in a tissue in the lungs; a cancer found in a tissue in the breast; a cancer found is the eyes; a cancer found in the liver; a cancer found in the prostate; or a cancer found in a tissue in the pancreas.

20. The method of any one of claims 15-19, wherein the treating decreases polyps, total adenoma counts, intestinal tumors, and/or cancer cell proliferation in the subject.

21. The method of any one of claims 15-20, wherein the treating increases cancer cell apoptosis and/or narcosis.

22. The method of any one of claims 15-21 , wherein the subject is a human subject.

Description:
CHEMOTHERAPEUTICALLY ACTIVE SACCHARIDE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This disclosure claims the benefit of priority to US. Provisional Application No.

62/343, 116, filed 10 August, 2016; 62/426,654, filed 28 November, 2016; and 62/464, 100, filed 27 February, 2017, which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] This disclosure is directed to a chemotherapeutically active composition derived from a chemotherapeutically inactive saccharide, a method of manufacture, a method of use, and treatment of a patient with the chemotherapeutically active composition.

BACKGROUND

[0003] Cancer is a group of varied diseases characterized by uncontrolled growth and spread of abnormal cells. Generally, all types of cancers involve some abnormality in the control of cell growth and division. The pathways regulating cell division and/or cellular communication become altered in cancer cells such that the effects of these regulatory mechanisms in controlling and limiting cell growth fails or is bypassed. Through successive rounds of mutation and natural selection, a group of abnormal cells, generally originating from a single mutant cell, accumulates additional mutations that provide selective growth advantage over other cells, and thus evolves into a cell type that predominates in the cell mass. This process of mutation and natural selection is enhanced by genetic instability displayed by many types of cancer cells, an instability which is gained either from somatic mutations or by inheritance from the germ line. The enhanced mutability of cancerous cells increases the probability of their progression towards formation of malignant cells. As the cancer cells further evolve, some become locally invasive and then metastasize to colonize tissues other than the cancer cell's tissue of origin. This property along with the heterogeneity of the tumor cell population makes cancer a particularly difficult disease to treat and eradicate.

[0004] Worldwide, more than 10 million people are diagnosed with cancer every year and it is estimated that this number will grow to 15 million new cases every year by 2020.

Cancer causes six million deaths every year or 12% of the deaths worldwide. There remains a need for methods that can treat cancer. These methods can provide the basis for pharmaceutical compositions useful in the prevention and treatment of cancer in humans and other mammals.

SUMMARY

[0005] A first embodiment is a chemotherapeutically active composition that includes a thermally activated saccharide selected from a thermally activated maltodextrin, a thermally activated fructose, and/or a thermally activated inulin.

[0006] A second embodiment is a chemotherapeutically active composition that includes a product obtained by exposing a maltodextrin, a fructose, and/or an inulin to a heat source until it is thermally activated.

[0007] A third embodiment is a composition that can include a thermally activated saccharide obtainable by exposing a maltodextrin, fructose, and/or inulin to a heat source until it is thermally activated

[0008] A fourth embodiments is a composition that can include the chemotherapeutically active composition described in any one of the prior embodiments and a pharmaceutically- acceptable carrier.

[0009] A fourth embodiment is a method of treating a subject that can include (a) identifying the subject presenting symptoms of cancer wherein said symptoms warrant treatment with a chemotherapeutic agent; (b) administering an effective amount the

chemotherapeutically active composition of any one of the prior embodiments; and, optionally (c) simultaneously, sequentially, or separately administering to the subject an effective amount a chemotherapeutic agent.

BRIEF DESCRIPTION OF THE FIGURES

[0010] For a more complete understanding of the disclosure, reference should be made to the following detailed description and accompanying drawing figures wherein:

[0011] Figure 1 shows cell narcosis and apoptosis for an HTC 1 16 control (Fig. 1A) and an HTC 116 control with PBS (Fig. 1 B);

[0012] Figure 2 shows cell narcosis and apoptosis for an HTC 1 16 cell line in the presence of unactivated and thermally treated saccharides with Fig 2A depicting the effects of glucose, Fig 2B the effects of thermally treated glucose; Fig 2C the effects of sucrose; Fig 2D the effects of thermally treated sucrose; Fig 2E the effects of fructose; and Fig 2F the effects of thermally treated fructose; [0013] Figure 3 shows cell narcosis and apoptosis for an HTC 1 16 cell line in the presence of unactivated and thermally treated saccharides with Fig 3A depicting the effects of clover honey, Fig 3B the effects of thermally treated clover honey; Fig 3C the effects of manuka honey; and Fig 3D the effects of thermally treated manuka honey;

[0014] Figure 4 shows cell narcosis and apoptosis for a healthy cell line (non- carcinomic) without thermally treated saccharide (Fig 4A) and with a thermally treated saccharide (Fig 4B)

[0015] Figure 5 is a table comparing Total Cell Death values (%) for unactivated and thermally activated materials against controls and blanks;

[0016] Figure 6 is a table comparing Total Cell Death values (%) for thermally activated fructoses; and

[0017] Figure 7 shows comparative cell death data for alterative cell lines (X-axis) in the absence of (basal level of cell death) and in the presence of 2 wt.% thermally activated saccharide (RMD-101) to the culture medium; where the base call death is held at a value of 1 and the effect of the thermally activated saccharide is shown as a factor thereto.

[0018] While specific embodiments are illustrated in the figures, with the understanding that the disclosure is intended to be illustrative, these embodiments are not intended to limit the invention described and illustrated herein.

DETAILED DESCRIPTION

[0019] This disclosure is directed to chemotherapeutically active compositions, their manufacture, and use with or without other chemotherapeutic agents. For clarity, the term chemotherapeutically active composition refers to a material that includes a thermally activated saccharide (a chemotherapeutically active saccharide) as will be described herein. The term chemotherapeutic agent(s) refers to chemical compositions that provide chemotherapeutic effects other than the herein recited chemotherapeutically active saccharides. Examples of chemotherapeutic agents are presented in Table 1.

[0020] As used herein, "comprising" means "including" and the singular forms "a", "an", or "the" include plural references unless the context clearly dictates otherwise. The term "or" refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. Ratios of materials are, herein, mass ratios (w/w, m/m, or wt.%/wt.%). [0021] Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting, unless otherwise indicated. Other features of the disclosure are apparent from the following detailed description and the claims.

[0022] Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, and so forth, as used in the specification or claims are to be understood as being modified by the term "about," even if this term is not expressly stated. Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that can depend on the desired properties sought and/or limits of detection under standard test conditions/methods. Furthermore, not all alternatives recited herein are equivalents.

[0023] Herein is disclosed a chemotherapeutically active composition that includes a thermally activated saccharide; a chemotherapeutically active saccharide produced by the thermal activation of a chemotherapeutically inactive saccharide. While there are a vast number of chemotherapeutically inactive saccharides, the thermal activation of saccharides to produce a chemotherapeutically active saccharide is limited to a small number of materials. Notably, the chemotherapeutically active saccharide can be a thermally activated maltodextrin, a thermally activated fructose, and/or a thermally activated inulin. Herein, a thermally activated saccharide is one that shows chemotherapeutic activity whereas the, respective, un-activated (e.g., unheated) saccharide is chemotherapeutically inactive. See for examples, Figures 1-6 showing cell death data for activated, unactivated, and saccharides that do not activate (e.g., glucose and sucrose).

[0024] In one instance, the chemotherapeutically active saccharide includes a thermally activated maltodextrin. Maltodextrins are saccharides typically comprised of 2 to 20 D-glucose units with a(1-4) glycosidic linkages. Herein, the maltodextrin can be the product from an amylase mediated digestion of a starch (e.g., corn starch). Preferably, the maltodextrin includes maltose, maltotriose, maltotetraose, maltopentaose, maltohexose, a product from an amylase mediated digestion of a starch, or a mixture thereof. More preferably, the maltodextrin includes maltose, maltotriose, maltotetraose, maltopentaose, and/or maltohexose. Even more preferably, the maltodextrin is selected from the group consisting of maltose, maltotriose, maltotetraose, maltopentaose, maltohexose, and a mixture thereof. Still more preferably, the maltodextrin includes maltose and/or maltotriose. Yet more preferably, the maltodextrin consists of maltose, maltotriose, or a mixture thereof. In another preferable instance, the thermally activated saccharide consists of the thermally activated maltodextrin.

[0025] In a second instance, the thermally activated saccharide consists of the thermally activated fructose. In a third instance, the thermally activated saccharide consists of the thermally activated inulin. In a fourth instance, the thermally activated saccharide consists of a plurality of: the thermally activated maltodextrin, the thermally activated fructose, and the thermally activated inulin.

[0026] Notably, the thermally activated maltodextrin, thermally activated fructose, and thermally activated inulin are, respectfully, products from the thermal activation of maltodextrin, fructose, and inulin. That is, the thermally activated maltodextrin is the product of the thermal activation of maltodextrin; the thermally activated fructose is the product of the thermal activation of fructose; and the thermally activated inulin is the product of the thermal activation of inulin. Importantly, the names thermally activated maltodextrin, thermally activated fructose, and thermally activated inulin are descriptive of the product and process of manufacture, the structure and composition of the thermally activated saccharide may or may not be inferred from the structure of the starting saccharide.

[0027] In another instance, the thermally activated saccharide, preferably, includes ions or compounds having molecular weights of about 324, 342, 486, and/or 504 daltons, as determined by mass spectroscopy. Notably, the molecular weights observed in the mass spec are dependent on the ionization matrix, ionization potential, and additional factors associated with the operation of the instrument. Herein the, preferred, molecular weights refer to those of the thermally activated saccharide, not the ion detected by mass spec. More preferably, the thermally activated saccharide is mono-dehydrated and, preferably, has a molecular weight selected from 324 and/or 486 daltons.

[0028] In still another instance, the thermally activated saccharide is active against the

HCT 116 epithelial cell line (human colon carcinoma). Preferably, the thermally activated saccharide provides an HCT 1 16 Cell Death of at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%. See for example Fig. 2F, Fig. 3B, Fig. 3D, Fig. 5, and Fig. 6. Herein, the Cell Death is the percentage of cells that have undergone narcosis or apoptosis after exposure to the compound (e.g., thermally activated saccharide). Preferably, the thermally activated saccharide is inactive against non-diseased cells (e.g. against non-carcinomic epithelial cells). In one instance, the thermally activated saccharide provides a Normal Cell Death of less than 25%, less than 20%, less than 15 %, less than 10%, or less than 5%. See Fig. 4A and 4B. Herein, the Normal Cell Death is the percentage of cells that have undergone narcosis or apoptosis after exposure to the thermally activated saccharide. Preferably, the Normal Cell Death is indistinguishable from a control that did not include the introduction of a thermally activated saccharide. In yet another instance, the thermally activated saccharide is active against melanoma and melanoma cell lines. See e.g., Fig. 7.

[0029] One example includes an adjuvant for the enhancement of cancer treatment which is obtainable by exposing a maltodextrin to a heat source until it is activated. Preferably, where the adjuvant is obtained by exposing a maltodextrin to a heat source until it is activated. More preferably, where the adjuvant is obtained by exposing a maltodextrin to a dry heat source until it is activated. In one instance, the heat source is between about 70 °C and about 150 °C. That is, the heat source raises the temperature of the maltodextrin to a temperature between about 70 °C and about 150 °C; alternatively, the heat source raises the temperature of an oven or container that holds the maltodextrin a temperature between about 70 °C and about 150 °C. In another instance, the temperature is between about 1 10 °C and about 130 °C. In still another instance, the temperature is about 120 °C. In an alternative instance, where the adjuvant is obtained by exposing a maltodextrin to a wet heat source until it is activated. In one instance, the heat source is water and the maltodextrin is heated to a temperature between about 90 °C and about 100 °C.

[0030] In one instance, the adjuvant is obtained by heating the maltodextrin, where the heating is conducted under substantially dry conditions. Herein, substantially dry means having a percent humidity of less than 50%, 40%, 30%, 20%, 10%, or 5%, more preferably, a percent humidity of less than 4%, 3%, 2%, or 1 %.

[0031] In another instance, the heating can be conducted for between about 1 minute and about 120 minutes. In another instance, the heating is conducted for about 1 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes. In another instance, the heating is conducted for at least 1 minute, at least about 5 minutes, or at least about 10 minutes. In another instance, the heating is conducted with agitation of the maltodextrin (e.g., stirring and/or tumbling).

[0032] Notably, the maltodextrin can be produced from an amylase mediated digestion of a polysaccharide. In one instance, the pre-digested polysaccharide includes about 300 to about 600 glucose units. In another instance, the polysaccharide is a product of a corn plant (e.g., corn starch).

[0033] In one instance, the adjuvant can be produced from the thermal treatment of the maltodextrin includes at least one D-glucose unit. In another instance the adjuvant is composed substantially of D-glucose unit but includes a thermally-formed active moiety.

[0034] Another example is a chemotherapeutically active saccharide consists of a product obtained by the process of heating a chemotherapeutically-inactive maltodextrin (1) at a temperature of about 1 10 °C to about 150 °C for a period of about 1 to about 120 minutes or (2) in water at a temperature of about 95 °C for a period of about 1 to about 120 minutes. Notably, the product is a result of a process that provides chemotherapeutic activity to a

chemotherapeutically-inactive material - not the enhancement of chemotherapeutic activity. Accordingly, the product is a chemical rearrangement of the starting maltodextrin not the thermal elimination of inert materials.

[0035] The chemotherapeutically active saccharide can include an active agent (i.e., an agent that provide the chemotherapeutic activity). In one instance, the active agent obtained from maltodextrin has an average molecular weight of about 535 to about 712 daltons, preferably an average molecular weight between 535 and 712 daltons, more preferably about 575, 600, 625, 650, 675, or 700 daltons. In another instance, the active agent comprises between 3 and 4 glucose units. That is, the active agent has a chemical structure/formula that is between a maltotriose and a maltotetraose. Preferably, the active agent is neither a maltotriose nor a maltotetraose but has a chemical formula between Ci 8 H 32 0i6 and C24H42O21 (e.g., has between 19 and 23 carbon atoms). In still another instance, the active agent is

chemotherapeutically active, that is the product obtained by the process of heating a

chemotherapeutically-inactive maltodextrin can be a combination of the active agent and inactive ingredients.

[0036] Yet another example includes an adjuvant for the enhancement of cancer treatment which is obtainable by exposing a 2-6 polysaccharide to a heat source until it is activated. Herein, a 2-6 polysaccharide is a disaccharide, trisaccharide, tetrasaccharide, pentasaccharide, hexasaccharide, or a mixture thereof. Preferably, the saccharide is glucose and the 2-6 polysaccharide is maltose, maltotriose, maltotetraose, maltopentaose, maltohexose, or a mixture thereof. [0037] Preferably, the adjuvant is obtained by exposing the 2-6 polysaccharide to a heat source until it is activated. More preferably, where the adjuvant is obtained by exposing the 2-6 polysaccharide to a dry heat source until it is activated. In one instance, the heat source is between about 70 °C and about 225 °C. Preferably, the heat source raises the temperature of the 2-6 polysaccharide to a temperature between about 100 °C and about 200 °C; alternatively, the heat source raises the temperature of an oven or container that holds the 2-6

polysaccharide a temperature between about 100 °C and about 200 °C. In another instance, the temperature is between about 110 °C and about 180 °C, about 120 °C and about 170 °C, about 130 °C and about 160 °C. In still another instance, the temperature is about 150 °C. In an alternative instance, where the adjuvant is obtained by exposing a 2-6 polysaccharide to a wet heat source until it is activated. In one instance, the heat source is water and the 2-6

polysaccharide is heated to a temperature between about 90 °C and about 100 °C.

[0038] In another instance, the adjuvant is obtained by heating the 2-6 polysaccharide, where the heating is conducted under substantially dry conditions. Herein, substantially dry means having a percent humidity of less than 50%, 40%, 30%, 20%, 10%, or 5%, more preferably, a percent humidity of less than 4%, 3%, 2%, or 1 %.

[0039] In yet another instance, the heating can be conducted for between about 1 minute and about 120 minutes. The heating can be conducted for about 1 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes. Preferably, the heating is conducted for at least 1 minute, at least about 5 minutes, or at least about 10 minutes. In another instance, the heating is conducted with agitation of the 2-6 polysaccharide (e.g., stirring and/or tumbling).

[0040] The chemotherapeutically active saccharide can be a thermally activated maltose, maltotriose, maltotetraose, maltopentaose, or maltohexose. Preferably, the

chemotherapeutically active saccharide is preferably a thermally activated 1 ,4 a-polyglucose. That is, the chemotherapeutically active saccharide is derived from a polysaccharide that, initially, was composed of 1 ,4 linkages between glucose molecules. In one preferable instance, the adjuvant is a thermally activated maltotriose. In another instance, the thermally activated maltotriose is the product of a thermal rearrangement of the terminal glucose. Preferably, the terminal glucose underwent a ring-opening reaction, a rearrangement, and then a ring closing reaction to provide the chemotherapeutically active saccharide. The chemotherapeutically active saccharide can have the same composition as the starting polyglucose but can include a thermally rearranged terminal glucose. In one instance, the thermally rearranged terminal glucose is shown in Formula 1

[0041] In another instance, thermally rearranged terminal glucose is shown in Formula 2

[0042] In Formula 1 and Formula 2, x is selected from the integers of 1-5. In one preferably instance X has the value of 2.

[0043] In still another instance, the thermal rearrangement of the terminal glucose results in the dehydration of the glucosidic termination. That is, the dehydration is the loss of one water molecule (H 2 0) form the formula. The thermal rearrangement can proceed through the (reversible) ring opening of the terminal glucose then a proton migration to produce a terminal en-diol. The en-diol can then lose the 3-hydroxide to yield an 2-enal.

[0044] The 2-enal can further rearrange to yield the terminations provided in Formula 3.

[0045] In still another instance, the thermal rearrangement of the terminal glucose can result in the formation of a terminal fructose. This instance thereby provides a glucose-glucose- fructose adjuvant from maltotriose. The other fructose adjuvants are analogously available from the other 2-6 polysaccharides.

[0046] In still yet another instance, the thermal rearrangement of the terminal glucose can result in the formation of a terminal mannose.

[0047] In yet another instance, the thermal rearrangement of the 2-6 polysaccharide can yield a cyclodextrin, in such instances, the thermal rearrangement can be of a 3-6 polysaccharide (e.g., maltrotriose to maltohexose). In one example of this instance, the thermal rearrangement can proceed through a 1 ,4 to 1 ,6 rearrangement of the glycosidic linkages.

[0048] In one example, the chemotherapeutically active saccharide is produced from the thermal treatment of the 2-6 polysaccharide includes at least one D-glucose unit. In another instance the adjuvant is composed substantially of D-glucose unit but includes a thermally- formed active moiety.

[0049] In a preferable example, the chemotherapeutically active saccharide is a thermally activated maltotriose. More preferably, the chemotherapeutically active saccharide consists essentially of the activated maltotriose. That is, that chemotherapeutically active saccharide is a chemical composition that is the thermally activated maltotriose but may contain a portion of unactivated maltotriose. Specifically, the chemotherapeutically active saccharide can be the product of the thermal activation of the maltotriose and can include both the thermally activated maltotriose (TAM) and the unactivated starting material (maltotriose) (uM). In one preferable example, the chemotherapeutically active saccharide consists essentially of the TAM and uM, preferably including about 5 to 95% of TAM and 5 to 95% of uM, more preferably including at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% TAM, where the remainder is uM. Notably and as is the case with chemical products, the chemotherapeutically active saccharide may include a small percentage of compositions that are not TAM or uM, preferably these inactive materials are included in percentages of less than 5%, 4%, 3%, 2%, or 1 %. In still another example, the chemotherapeutically active saccharide is (consists of) the thermally activated maltotriose. Preferably, wherein the chemotherapeutically active saccharide is the isolated and purified TAM.

[0050] Still yet another embodiment is a chemotherapeutically active saccharide of a product obtained by the process of heating a chemotherapeutically-inactive 2-6 polysaccharide (1) at a temperature of about 1 10 °C to about 200 °C for a period of about 1 to about 120 minutes or (2) in water at a temperature of about 95 °C for a period of about 1 to about 120 minutes. Notably, the product is a result of a process that provides chemotherapeutic activity to a chemotherapeutically-inactive material - not the enhancement of chemotherapeutic activity. Accordingly, the product is a chemical rearrangement of the starting 2-6 polysaccharide not the thermal elimination of inert materials.

[0051] A chemotherapeutically active product can include an active agent (i.e., an agent that provides the chemotherapeutic activity). In one instance, the active agent, derivable from maltose, has a molecular weight of about 324 daltons, in another instance 342 daltons. In still another instance the active agent is a mixture of products wherein a first agent has a molecular weight of about 324 daltons and the second agent has a molecular weight of about 342 daltons. In another instance, the active agent comprises two glucose units. In still another instance, the active agent comprises a mono-dehydrated maltose. Notably, the molecular weight of the active agent can be determined by mass spectroscopy, depending on the matrix and launch procedure, the molecular weight determined by mass spectroscopy can be that of the ionized salt. For example, in this instance, the active agent may appear as a signal at about 347 and/or about 365 m/z.

[0052] In another instance, the active agent, derivable from maltotriose, has a molecular weight of about 486 daltons, in another instance 504 daltons. In still another instance the active agent is a mixture of products wherein a first agent has a molecular weight of about 486 daltons and the second agent has a molecular weight of about 504 daltons. In another instance, the active agent comprises 3 glucose units. In still another instance, the active agent comprises a mono-dehydrated maltotriose. Notably, the molecular weight of the active agent can be determined by mass spectroscopy, depending on the matrix and launch procedure, the molecular weight determined by mass spectroscopy can be that of the ionized salt. For example, in this instance, the active agent may appear as a signal at about 509 and/or about 527 m/z.

[0053] In another instance, the active agent, derivable from maltotetraose, has a molecular weight of about 648 daltons, in another instance 666 daltons. In still another instance the active agent is a mixture of products wherein a first agent has a molecular weight of about 648 daltons and the second agent has a molecular weight of about 666 daltons. In another instance, the active agent comprises 4 glucose units. In still another instance, the active agent comprises a mono-dehydrated maltotetraose. Notably, the molecular weight of the active agent can be determined by mass spectroscopy, depending on the matrix and launch procedure, the molecular weight determined by mass spectroscopy can be that of the ionized salt. For example, in this instance, the active agent may appear as a signal at about 671 and/or about 689 m/z.

[0054] In another instance, the active agent, derivable from maltopentaose, has a molecular weight of about 811 daltons, in another instance 829 daltons. In still another instance the active agent is a mixture of products wherein a first agent has a molecular weight of about 81 1 daltons and the second agent has a molecular weight of about 829 daltons. In another instance, the active agent comprises 5 glucose units. In still another instance, the active agent comprises a mono-dehydrated maltopentaose. Notably, the molecular weight of the active agent can be determined by mass spectroscopy, depending on the matrix and launch procedure, the molecular weight determined by mass spectroscopy can be that of the ionized salt. For example, in this instance, the active agent may appear as a signal at about 834 and/or about 852 m/z.

[0055] In another instance, the active agent, derivable from maltohexaose, has a molecular weight of about 973 daltons, in another instance 991 daltons. In still another instance the active agent is a mixture of products wherein a first agent has a molecular weight of about 973 daltons and the second agent has a molecular weight of about 991 daltons. In another instance, the active agent comprises 6 glucose units. In still another instance, the active agent comprises a mono-dehydrated maltohexaose. Notably, the molecular weight of the active agent can be determined by mass spectroscopy, depending on the matrix and launch procedure, the molecular weight determined by mass spectroscopy can be that of the ionized salt. For example, in this instance, the active agent may appear as a signal at about 996 and/or about 1014 m/z.

[0056] One preferred example is a chemotherapeutically active saccharide that includes a thermally activated fructose. Preferably, the thermally activated fructose has a molecular weight of about 486 or 504 daltons. Alternatively, the thermally activated fructose can be a mixture of polysaccharides; the polysaccharides having molecular weights selected from about 324, 342, 486, and 504 daltons. In one instance, the thermally activated fructose can be a mono-dehydrated polysaccharide; preferably having at a molecular weight selected from 324 and 486 daltons. In one instance, the thermally activated fructose is the product of thermal activation of fructose (as described below). In another instance, the thermally activated fructose is the product of thermal activation of a material that includes fructose or provides fructose during heating. In yet another instance, the thermally activated fructose is the product of thermal activation of a sugar mixture that includes at least 25%, 50%, or 75 % fructose; a high fructose corn syrup (e.g., HFCS 42, HFCS 55, HFCS 65, or HFCS 90); and/or honey.

[0057] Another preferred examples is a chemotherapeutically active saccharide that includes a product obtainable by exposing fructose to a heat source until it is thermally activated. In one instance, the product is obtainable by exposing fructose to a dry heat source; wherein the heat source is between about 110 °C and about 210 °C; between about 120 °C and about 180 °C, about 120 °C, about 130 °C, about 140 °C, about 150 °C, about 160 °C, or about 170 °C. In another instance, the product is obtainable by exposing fructose to a wet heat source; wherein the heat source is about 100 °C, 1 10 °C, 120 °C, or 130 °C (e.g., steam).

[0058] Thermal activation of fructose can include a dimerization and/or trimerization of the fructose; that is, the formation of a dimer and/or trimer product. In one instance, the thermal activation further includes mono-dehydration of the dimer or trimer product.

[0059] The thermally activated fructose can be obtained by the thermal activation of inulin and/or compositions that include inulin (preferably, wherein inulin is a majority of the composition). In this instance, the thermally activated fructose can be a mixture of

polysaccharides; the polysaccharides including those having molecular weights selected from about 324, 342, 486, and 504 daltons. In another instance, the thermally activated fructose can be a mono-dehydrated polysaccharide; preferably having at a molecular weight selected from 324 and 486 daltons. The chemotherapeutically active composition can include a product obtained by exposing inulin to a heat source until it is thermally activated. In one instance, the product is obtainable by exposing inulin to a dry heat source; wherein the heat source is between about 1 10 °C and about 210 °C; between about 120 °C and about 180 °C, about 120 °C, about 130 °C, about 140 °C, about 150 °C, about 160 °C, or about 170 °C. In another instance, the product is obtainable by exposing inulin to a wet heat source; wherein the heat source is about 110 °C, 120 °C, or 130 °C. In one example, thermal activation of inulin includes the formation of dimers and/or trimers of fructose. In yet another instance, the thermal activation further includes mono-dehydration of the dimer or trimer product.

[0060] The thermally activated fructose can be obtained by the thermal activation of high fructose corn syrup. In this instance, the thermally activated fructose can be a mixture of polysaccharides; the polysaccharides including those having molecular weights selected from about 324, 342, 486, and 504 daltons. In another instance, the thermally activated fructose can be a mono-dehydrated polysaccharide; preferably having at a molecular weight selected from 324 and 486 daltons. The chemotherapeutically active composition can include a product obtained by exposing high fructose corn syrup to a heat source until it is thermally activated. In one instance, the product is obtainable by exposing high fructose corn syrup to a dry heat source; wherein the heat source is between about 1 10 °C and about 210 °C; between about 120 °C and about 180 °C, about 120 °C, about 130 °C, about 140 °C, about 150 °C, about 160 °C, or about 170 °C. In another instance, the product is obtainable by exposing high fructose corn syrup to a wet heat source; wherein the heat source is about 1 10 °C, 120 °C, or 130 °C. In one example, thermal activation of high fructose corn syrup includes the formation of dimers and/or trimers of fructose. In yet another instance, the thermal activation further includes mono- dehydration of the dimer or trimer product.

[0061] Still another embodiment is a composition that can include the

chemotherapeutically active composition, described above, and a pharmaceutically-acceptable carrier.

[0062] Yet another embodiment is a method of treating a subject with the herein described chemotherapeutically active saccharide. The method can include (a) identifying the subject presenting symptoms of cancer wherein said symptoms warrant treatment with a chemotherapeutic agent and (b) administering an effective amount the chemotherapeutically active composition (e.g., the chemotherapeutically active saccharide or a combination thereof with, for example, carriers or diluents). The process can optionally further include (c) simultaneously, sequentially, or separately administering to the subject an effective amount a chemotherapeutic agent (e.g., those chemotherapeutic agents provided in Table 1). Preferably and during the identification step (a), it is determined that at least one of the chemotherapeutic agent listed in Table 1 would be beneficial for the treatment of the subject. Even more preferably, the subject's symptoms of cancer have been shown to more effectively reduced by treatment with the chemotherapeutic agent of step (c) and the chemotherapeutically active composition than by the chemotherapeutic agent of step (c) alone in a controlled study comparing the effectiveness of the chemotherapeutic agent of step (c) and the effectiveness of chemotherapeutic agent of step (c) and the chemotherapeutically active composition.

[0063] The chemotherapeutically active composition can be administered orally, buccally and/or by oral inhalation. In one instance, the chemotherapeutically active composition can be administered subcutaneously, parenterally, transdermal^, intraperitoneally,

intramuscularly, by suppository, by implantation, by intravesical instillation, by intraocularly instillation, by intracavitary instillation, by intraarterially instillation, by intralesionally instillation, or by application to non-nasal, non-buccal mucous membranes. In another instance, the chemotherapeutically active composition is administered nasally, by nasal inhalation, by intranasal instillation, by implantation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, transdermal^, or by application to nasal mucous membranes. In yet another instance, the chemotherapeutically active composition is administered topically.

[0064] The cancer of step (a) can be further diagnosed as a carcinoma; a sarcoma; a melanoma; a lymphoma; a leukemia; a brain tumor; a cancer found in the blood; a cancer found in a tissue in the skin; a cancer found in a tissue in the lungs; a cancer found in a tissue in the breast; a cancer found is the eyes; a cancer found in the liver; a cancer found in the prostate; or a cancer found in a tissue in the pancreas. The method can be used to treat or decrease polyps, total adenoma counts, intestinal tumors, and/or cancer cell proliferation in the subject.

Preferably, wherein the treating increases cancer cell apoptosis and/or narcosis. More preferably, wherein the subject is a human subject.

[0065] Yet another embodiment is a composition that includes any of the above described adjuvants and a pharmaceutically-acceptable carrier. In one instance, the

composition further includes an effective amount of one or more chemotherapeutic agents selected from Table 1. In still another instance, the composition further includes a second agent selected from the group consisting of one or more anti-inflammatory agents, antidiabetic agents, hypolipidemic agents, additional chemotherapeutic agents selected from Table 1 , antiviral agents, antibiotics, metabolic agents, small molecule inhibitors, protein kinase inhibitors, adjuvants, apoptotic agents, anti-proliferative agents, and organotropic targeting agents, and combinations thereof.

Table I

' / ' hen peutic A qents

Alkyl sufonates MEHD7945 A AT9283 XL228 BI 847325 GSK2636771 HMPL-013

Ethylenimines MM-151 ENMD-2076 TSU 68, CI- 1040 PF-4691502 KRN951,

Nitrogen mustard RO5083945, MK5108 SU6668 GDC-0623 PI- 103 AV-951

Nitrosoureas GA201 MLN8237 ENMD-2076 GDC-0973 PKI-587 MGCD265

Platinum analogues Sym004 PF-03814735 AC220 GSK1120212 PWT33597 AEE788,

Triazenes OMP-18R5 TAK901 AP24534 MEK162 PX-866 NVP-

Folate antagonists MGAH22 AS703569, AS703569, PD0325901, SF1126 AEE788

Purine analogues MM-111 R763 R763 PD-0325901 XL147, AP24534

Pyrimidine MOAB 2C4 AT9283 CEP-701 R05126766 SAR245408 AZD2171 analogues PR0132365 AZD1152- ENMD-0276 TAK-733 XL765, AZD6474,

Epothilones AV 203 HQPA, MLN518, AMG 208 SAR245409 ZD6474

Halichondrin B MEHD7945 A AZD1152 CT53518 AMG 337 BYL719 BAY 43- analogue MM-111 GSK1070916 MP-470 ARQ 197 GDC-0032 9006

Taxanes MM-121, PF-03814735 PKC412 BMS-777607 INK-1117 BMS-582664

Vinca alkaloids SAR256212 GSK1070916 PLX3397, EMD CAL-101, GS- BMS-

Cephalotaxine U3-1287, AMG AMG900 PLX108-01 1214063 1101 690514,

Camptothecin 888 BI 847325 SU-11248 EXEL-2880, LY317615 EVRI derivatives AMG 102 PHA-739358 XL184 GSK1363089, PKC412 E7080

Quinoline alkaloids AV-299, SNS-314 AEE788, NVP- XL880 LY317615 PKC412

Anthracene dione SCH900105 ARQ 736 AEE788 HMPL-504 LY317615 RAF265

Anthracyclines AMG-479 GSK2118436 ARRY 380 INCB028060, LY317615 SU-11248

Epipodophyllotoxins BI 836845 PLX-4032, BIBW-2992 INC280 BI 6727 XL184

Antitumor antibiotic BIIB022 RG7204, CI-1033, MGCD265 BI 2536 XL820

Aspariginase CP-751871 R05185426 PD183805 MK-2461 GSK461364, YN968D1 derivatives EV1C-A12 RAF265 GSK572016, MP-470 GSK-461364 BAY 57-

Hypomethylating MEDI-573 R05212054, GW2016, GW- PF-02341066 NMS- 9352

Agents MK-0646 PLX3603 572016 PF-04217903 1286937 E7080

Retinoic acid BI 836845 AS703569, HKI-272 XL184 ON 01910.Na AMG 386 derivatives MEDI-573 R763 TAK 165 MGCD265 BAY 43-9006 ABT-263,

Telomerase template BMS-986015 AVL-292 XL647, KD019 AP23573, BAY 73-4506 ABT-737 antagonist ABT-700 PCI-32765 BMS-536924 MK8669 LGX818 AT 101

CP675,206 LY2875358 HMR-1275, BMS-754807 AY 22989, MLN2480 GDC-0199,

MDX-010, MDX- MetMAb, L868275, OSI-906 SILA 9268A, R05126766 ABT-0199,

101, BMS-734016 R05490258, flavopiridol XL228 WY-090217 XL281, BMS- RG7601

GTX-024 OA-5D SCH727965 AZD1480 AZD8055 908662 GX15-070

MDV3100 AMP-224 CYC202 CYT-387 BEZ235, AMG706 G3139

CGS 20267 BMS-936558, LEE011 INCBO 18424 NVP-BEZ235 AZD6474, LY2510924

FCE-24304 MDX-1106, LY2835219 AT9283 BGT226, ZD6474 EPZ-5676

LY- 139481 ONO-4538 PD 0332991 BMS-911543 NVP-BGT226 BAY 43-9006 EPZ-6438,

R-1569 CT-011 PLX3397, CEP-701 CCI-779 BAY 73-4506 E7438

ACZ885 MK-3475 PLX108-01 SAR302503, GDC-0980 MP-470 IND 58359

BMS-986015 MDX-1105, AEE788, TG101348 MLN0128, SU-11248 MK0752

AMP-224 BMS-936559 NVP- SB 1518 INK128 XL184 FK228

BMS-936558, MPDL3280A, AEE788 XL019 OSI-027 PF-02341066 LBH589

MDX-1106, ONO- RG7446 AP26113 SB 1518 PF-4691502 AB 1010 MK-0683

4538 EVIC-3G3 AZD6474, LY2784544 PI- 103 AZD0530 MS-275,

CT-011 MEDI-575 ZD6474 XL019 PKI-587 BMS-354825 SNDX-275

MK-3475 AMG951, AZD9291 CP-690550 PWT33597 KX2-391 PXD101

MDX-1105, BMS- rhApo2L/TRAIL BIBW-2992 AB 1010 RAD001 XL228 OGX-427

936559 HGS-ETR1 BPI-2009H AG-013736 SF1126 R788 SAR405838,

MPDL3280A, AMG-655 CI-1033, AMG706 XL765, MGCD265 MI-773

RG7446 HGS-ETR2 PD 183805 AS703569, SAR245409 XL184 17-AAG,

APC8015 LBY135 CO-1686 R763 AMG706 LY2157299 KOS-953

TheraCys PRO95780 HMPL-813 BAY 57-9352 BIBF1120 AZD8055 AT13387

TSF EVIC-1121B MNPL-309 BAY 73-4506 GW786034 MLN0128, AUY922

KW-0761 AMN107 OSI-774, CP- BMS-354825 MLN518, INK128 Debio 0932

MT103, MT-103, AP24534 258,774 GW786034 CT53518 OSI-027 IPI-504

MEDI-538 AS703569, XL647, MLN518, X-82 ABT-869 STA-9090

GA101 R763 KD019 CT53518 CP-868569 ENMD-2076 XL888 IDEC-102, IDEC- AT9283 ZD1839 MP-470 MP-470 EXEL-2880, MK0752

C2B8 BMS-354825 AZD8931 PKC412 PKC412 GSK1363089, PF-03084014

IDEC Y2B8 INNO-406, NS- BMS-599626, PLX3397, ABT-869 XL880 REGN421

CAT-8015 187 SKI-606 AC480 PLX108-01 AG-013736 HMPL-012 RO4929097,

SGN-35 STI-571, BMS-690514, STI-571, BAY 43-9006 PTK 787, R4733

Campath CGP57148, EVRI CGP57148, BAY 57-9352 CGP 79787, ABT-888

IMGN901 CGP57148B EKB-569 CGP57148B BAY 73-4506 ZK 222584 AG-014699, hLLl XL228 HM781-36B SU-11248 SU-11248 TSU 68, PF-01367338

TRC105 AS703569, PF-00299804 XL184 TSU 68, SU6668 AZD2281

BMS 663513 R763 XL647, XL820 SU6668 X-82 BMN 673

MORAb-004 AZD5363 KD019 INNO-406, XL820 XL647, BSI-201

CP675,206 GDC-0068 AB 1010 NS-187 BAY 80-6946 KD019 MK4827

MDX-010, MDX- GSK2110183 GSK2256098 AS703569, BEZ235, AG-013736 CS 7017,

101, BMS-734016 MK-2206 VS-4718 R763 NVP-BEZ235 AMG706 RS5444

MEGF0444A AP26113 VS-6063 BVD-523 BGT226, BAY 73-4506 LDP 341,

ABT-806, mAb-806 ASP3026 AB 1010 MK-8353, NVP-BGT226 BIBF1120 MLN341,

ABX-EGF CH5424802, AP24534 SCH900353 BKM120 E-3810 PS-341 h-R3, TheraCIM AF802 AZD4547 AS703026, BYL719 GW786034 PR-171

IMC-11F8 LDK378 BGJ398, MSC1936369B GDC-0941 GDC-0449

IMC-C225 PF-02341066 NVP-BGJ398 AZD6244, GDC-0980 GDC-0449

TSR-011 BIBF1120 ARRY-142886 LDE225

X-396 E-3810 AZD8330 LY2940680

AS703569, HMPL-012 BAY 86-9766, CC-4047

R763 TKI258, RDEA119 CC-5013

CHIR-258