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Methods, compositions and articles of manufacture for contributing to the treatment of cancersRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain StructureMethods, compositions and articles of manufacture for contributing to the treatment of cancers description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070032422, Methods, compositions and articles of manufacture for contributing to the treatment of cancers. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of U.S. patent application Ser. No. 11/360,236 filed Jun. 28, 2006 (which claims the benefit of U.S. Provisional Patent Application Nos. 60/655,656; 60/655,654; and 60/655,643 all of which were filed on Feb. 22, 2005) which is a continuation-in-part of U.S. patent application Ser. No. 10/691,915 filed Oct. 23, 2003 which claims the benefit of U.S. provisional patent application No. 60/420,960, filed Oct. 24, 2002. The contents of all these applications are incorporated by reference herein in their entirety. FIELD OF THE INVENTION [0002] The present invention relates to methods, compositions and articles of manufacture for contributing to the treatment of cancers including solid tumors through administration of an endothelin agonist and a chemotherapeutic agent. BACKGROUND OF THE INVENTION [0003] Successful treatment of cancers, including solid tumors, remains an unfulfilled medical goal, despite increased understanding of the molecular biology of tumor cells and the availability of an increased number of potential therapeutic agents. For example, breast cancer incidence has increased substantially in the last 10 years, and is the single leading cause of death for women ages 40-49 years in the United States. [0004] One problem in the treatment of cancers is that an effective dose of a wide variety of potential chemotherapeutic agents is restricted by these agents' non-selective, highly toxic effect on normal tissues. As a result, many patients suffer from the side effects of chemotherapy without reaping the benefits of the treatment. For example, the chemotherapeutic agent paclitaxel inhibits cellular proliferation and induces apoptosis of tumor cells. The clinical utility of paclitaxel has been hampered, however, by its dose limiting toxicities including hypersensitivity, neutropenia and peripheral neuropathy. Thus, there is a necessity to develop more specific and less toxic cancer therapies. [0005] Targeted delivery of chemotherapeutic agents to tumors could have the advantage of enhancing the benefit of chemotherapeutic agents while minimizing their systemic toxic effects. Such targeted delivery could also serve to lower the required dose of chemotherapeutic agents thus potentially reducing the unacceptable adverse effects of these agents. One possible way to achieve targeted delivery of chemotherapeutic agents is to utilize the distinctive features of tumor vasculature. [0006] Tumors greater than a few millimeters in size require a constant nutrient supply, and, therefore, develop their own vascular bed and blood flow. Folkman, Cancer Res, 46:467 (1986). Without constant nourishment from these developing blood vessels, the tumors become hypoxic and subsequently die. Recruitment of new vasculature from preexisting blood vessels is termed "angiogenesis." [0007] During angiogenesis, tumor blood vessels develop substantially differently from normal vasculature, and have different properties. Single layered epithelial cells are the first hastily formed tumor blood vessels. These newly formed tumor blood vessels do not have a smooth muscle layer or innervation. Tumors also incorporate mature blood vessels that possess all their autoregulatory functions. Mattsson et al., Tumor Blood Circulation, CRC Press, Boca Raton, pg. 129 (1979); Reinhold, Tumor Blood Circulation, CRC Press, Boca Raton, pg. 115 (1979); Warren, Tumor Blood Circulation, CRC Press, Boca Raton, pg. 26 (1979). [0008] Vascular tone (the degree to which blood vessels are dilated or constricted) is governed by a host of endogenous factors including H.sup.+, K.sup.+, Ca.sup.2+, pO.sub.2, pCO.sub.2 and nitric oxide (NO), as well as other regulatory substances such as endothelin (ET-1). Secombe et al., Landes, Austin, pg. 40 (1994); Luscher et al., The endothelium: modulator of cardiovascular function, CRC Press, Boca Raton, pg. 61 (1990). ET-1 contributes significantly to regulating vascular tone (Yanagisawa et al., Nature, 332:411 (1988)) and investigators have shown an increase in ET1 and ET.sub.B receptor expression in solid tumors including breast carcinomas. Alanen et al., Histopathology, 36:161 (2000); Nelson et al., Cancer Res, 56:663 (1996); Kar et al., Biochem Biophys Res Commun 216:514 (1995); Pagotto etal., J Clin Invest, 96:2017 (1995); Yamashita et al., Cancer Res, 52:4046 (1992); Yamashita et al., Res Commun Chem Pathol Pharmacol, 74:363 (1991). Further, stimulation of ET.sub.B receptors causes an increase in blood supply to tumors through vasodilation of tumor blood vessels. The present invention takes advantage of this fact by using ET.sub.B receptor agonists to selectively increase blood flow to tumors to enhance the targeted delivery of chemotherapeutic agents. SUMMARY OF THE INVENTION [0009] The present invention is directed to the administration of endothelin agonists and a chemotherapeutic agent to contribute to the treatment of cancers including solid tumors. In particular, tumors have distinctive vasculature including an increased number of ET.sub.B receptors which, when bound, cause vasodilation. Because ET.sub.B receptors are vasodilators, an ET.sub.B receptor agonist, in combination with a chemotherapeutic agent, is useful in the treatment of a solid tumor, such as those found in breast cancers. The ET.sub.B receptor agonist can more effectively deliver chemotherapeutic agents to tumors resulting in enhanced treatment. [0010] Specifically, one embodiment according to the present invention includes a method of contributing to the treatment of a cancer comprising administering an ET.sub.B agonist and a chemotherapeutic agent. In various embodiments of the methods according to the present invention, the ET.sub.B agonist and the chemotherapeutic agent can be administered substantially simultaneously or can be administered sequentially (with the chemotherapeutic agent administered prior to the ET.sub.B agonist or the ET.sub.B agonist administered prior to the chemotherapeutic agent). In certain embodiments according to the present invention when the ET.sub.B agonist and the chemotherapeutic agent are administered substantially simultaneously, they can be administered as a single composition. [0011] Another embodiment according to the present invention includes a composition comprising a chemotherapeutic agent, an ET.sub.B agonist, and an optional excipient. Another embodiment according to the present invention includes an article of manufacture comprising a composition comprising an ET.sub.B agonist, and instructional information directing the administration of the composition with a chemotherapeutic agent to treat a solid tumor. Articles of manufacture according to the present invention can further comprise one or more chemotherapeutic agents. When articles of manufacture according to the present invention include one or more chemotherapeutic agents, the ET.sub.B agonist and the chemotherapeutic agent can be part of the same composition, can be provided as separate compositions, or both. [0012] Cancers that are treated with the methods, compositions or articles of manufacture according to the present invention can include solid tumors including, without limitation, ovarian tumors, colon tumors, Kaposi's sarcoma, breast tumors, melanoma, prostate tumors, meningiomas, liver tumors, breast phyllode tumors and combinations thereof. [0013] Endothelin B agonists used in accordance with the methods, compositions or articles of manufacture of the present invention can selectively increase blood supply to solid tumors thus increasing the delivery of chemotherapeutic agents to the solid tumor. Endothelin B agonists that can be used in accordance with the present invention can include, without limitation, one or more of ET-1, ET-2, ET-3, BQ3020, IRL1620 (N-suc-[Glu9, Ala11,15]ET-1 (8-21)), sarafotoxin 56c, [Ala1, 3, 11, 15]ET-1, and combinations thereof. Chemotherapeutic agents can include, without limitation, one or more of adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin, doxorubicin, alpha interferon, beta interferon, gamma interferon, interleukin 2, irinotecan, docetaxel, paclitaxel, topotecan, 5-fluorouracil, and combinations thereof. Particular methods, compositions or articles of manufacture according to the present invention will include IRL1620 as the ET.sub.B agonist with a chemotherapeutic agent selected from the group consisting of paclitaxel, doxorubicin, 5-fluorouracil, and combinations thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG. 1 shows the effect of IRL1620 on paclitaxel-induced changes in tumor perfusion; [0015] FIGS. 2A-2E show the effect of ET-1 on systemic hemodynamics of cancer-free and breast tumor-bearing rats; [0016] FIGS. 3A-3B show the effect of ET-1 on blood flow and regional vascular resistance in the breast tissue of cancer-free and breast tumor-bearing rats; [0017] FIGS. 4A-4C show the effect of ET-1 on perfusion, concentration of moving blood cells (CMBC), and velocity of blood cells in breast tissue of cancer-free and breast tumor-bearing rats; [0018] FIGS. 5A-5C show the effect of BQ788 on ET-1-induced changes in blood perfusion, CMBC, and velocity of blood cells in breast tissue of cancer-free and breast tumor-bearing rats; [0019] FIG. 6 shows the effect of vehicle or IRL1620 on plasma pharmacokinetics of paclitaxel analysis in normal and tumor bearing rats as determined by HPLC; Continue reading about Methods, compositions and articles of manufacture for contributing to the treatment of cancers... 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