EP1858539A2 - Methodes, compositions et articles manufactures destines a contribuer au traitement de tumeurs solides - Google Patents

Methodes, compositions et articles manufactures destines a contribuer au traitement de tumeurs solides

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Publication number
EP1858539A2
EP1858539A2 EP06748250A EP06748250A EP1858539A2 EP 1858539 A2 EP1858539 A2 EP 1858539A2 EP 06748250 A EP06748250 A EP 06748250A EP 06748250 A EP06748250 A EP 06748250A EP 1858539 A2 EP1858539 A2 EP 1858539A2
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European Patent Office
Prior art keywords
tumor
chemotherapeutic agent
agonist
paclitaxel
irl1620
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EP06748250A
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German (de)
English (en)
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Anil Gulati
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University of Illinois
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University of Illinois
Spectrum Pharmaceuticals Inc
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Publication of EP1858539A2 publication Critical patent/EP1858539A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2285—Endothelin, vasoactive intestinal contractor [VIC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to methods, compositions and articles of manufacture for contributing to the treatment of solid tumors, such as breast tumors, in a mammal, through administration of an endothelin agonist and a chemotherapeutic agent.
  • chemotherapeutic agents 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 necessity to develop more specific and less toxic cancer therapies.
  • 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.
  • 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.”
  • 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).
  • Vascular tone (the degree to which blood vessels are dilated or constricted) is governed by a host of endogenous factors including H + , K + , Ca 2+ , p ⁇ 2 , pCO 2 and nitric oxide (NO), as well as other regulatory substances such as endothelin (ET-1). Secombe et al., 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 ETB receptor expression in solid tumors including breast carcinomas.
  • ETB receptors stimulate an increase in blood supply to tumors through vasodilation of tumor blood vessels.
  • the present invention takes advantage of this fact by using ETB receptor agonists to selectively increase blood flow to tumors to enhance the targeted delivery of chemotherapeutic agents.
  • the present invention is directed to the administration of endothelin agonists and a chemotherapeutic agent to an individual in need thereof to contribute to the treatment of a solid tumor.
  • tumors have distinctive vasculature including an increased number of ETB receptors which, when bound, cause vasodilation.
  • ETB receptors are vasodilators
  • an ETB 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 ETB receptor agonist can more effectively deliver chemotherapeutic agents to tumors resulting in enhanced treatment.
  • one embodiment of the present invention includes a method of contributing to the treatment of a solid tumor comprising intravenously administering to a mammal in need thereof an ETB agonist and a chemotherapeutic agent, wherein the ET 6 agonist selectively increases blood supply to the solid tumor thus increasing the delivery of the chemotherapeutic agent to the solid tumor.
  • the pharmacokinetics of the chemotherapeutic agent are not affected by the ET 8 receptor agonist.
  • the ET B receptor agonist enhances the efficacy of the chemotherapeutic agent.
  • the ETB agonist is selected from the group consisting of ET-1 , ET-2, ET-3, BQ3020, IRL1620 (N-SUC-[GIu 9 , Ala 11l15 ]ET-1 (8-21)), sarafotoxin 56c, [AIa 1 ' 3 ' 11 ' 15 ]ET-1 , and mixtures thereof.
  • the ETB agonist is IRL1620.
  • the chemotherapeutic agent is selected from the group consisting of adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin, doxorubicin, alpha interferon, beta interferon, gamma interferon, interleukin 2, irinotecan, docetaxel, paclitaxel, topotecan, and mixtures thereof.
  • the chemotherapeutic agent is paclitaxel.
  • the solid tumor is selected from the group consisting of an ovarian tumor, a colon tumor, Kaposi's sarcoma, a breast tumor, a melanoma, a prostate tumor, a meningioma, a liver tumor, and a breast phyllode tumor.
  • the solid tumor is a breast tumor.
  • the ETB agonist and the chemotherapeutic agent are administered according to a strategy selected from the group consisting of administering the ET 8 agonist and the chemotherapeutic agent as a single composition; administering the ETB agonist and the chemotherapeutic agent as separate compositions; administering the ETB agonist and the chemotherapeutic agent sequentially with the ET B agonist administered before the chemotherapeutic agent; and administering the ET B agonist and the chemotherapeutic agent sequentially with the chemotherapeutic agent administered before the ETB agonist.
  • the mammal is a human.
  • the present invention also includes articles of manufacture.
  • the article of manufacture comprises (a) a packaged composition comprising an ET B agonist, and; (b) an insert providing instructions for the intravenous administration of the ETB agonist to contribute to the treatment of a solid tumor in a mammal; and (c) a container for the (a) ETB agonist and (b) the insert.
  • the article of manufacture further comprises (d) a chemotherapeutic agent, and the instructions provide for the administration of the ETB agonist and the chemotherapeutic agent and the container (c) is for (a) the ET 8 agonist, (b) the insert, and (d) the chemotherapeutic agent.
  • the ET B agonist when the instructions are followed, selectively increases blood supply to the solid tumor thus increasing the delivery of the chemotherapeutic agent to the solid tumor.
  • the pharmacokinetics of the chemotherapeutic agent are not affected by the ETB receptor agonist.
  • the ETB receptor agonist enhances the efficacy of the chemotherapeutic agent.
  • the ET 6 agonist is selected from the group consisting of ET-1 , ET-2, ET-3, BQ3020, IRL1620 (N-SUC-[GIu 9 , Ala 11
  • the ETB agonist is IRL1620.
  • the chemotherapeutic agent is selected from the group consisting of adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin, doxorubicin, alpha interferon, beta interferon, gamma interferon, interleukin 2, irinotecan, docetaxel, paclitaxel, topotecan, and mixtures thereof.
  • the chemotherapeutic agent is paclitaxel.
  • FIG. 1 shows the effect of IRL1620 on paclitaxel-induced changes in tumor perfusion
  • FIGS. 2A-2E show the effect of ET-1 on systemic hemodynamics of cancer-free and breast tumor-bearing rats
  • 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;
  • 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;
  • 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;
  • FIG. 6 shows the effect of IRL1620 on paclitaxel accumulation in tumor and other major organs of breast tumor-bearing rats;
  • FIG. 7 shows the effect of vehicle or IRL1620 on plasma pharmacokinetics of paclitaxel analysis in normal and tumor bearing rats as determined by HPLC;
  • FIGS. 8 and 9 show the effect of vehicle or IRL1620 on plasma pharmacokinetics of [ 3 H]-paclitaxel as determined by liquid scintillation counting;
  • FIGS. 10A and 10B show the effect of IRL1620 on breast tumor perfusion as measured by Laser Doppler Flowmetry
  • FIG. 11 shows the time dependent effect of IRL1620 administration on [ 3 H] paclitaxel concentration in tumor and major organs of breast tumor bearing rats;
  • FIG. 12 shows the percentage difference in the body weight of breast tumor bearing rats compared to the beginning of treatment
  • FIG. 13 shows the effect of IRL1620 administration on the tumor volume of breast tumor bearing rats.
  • FIG. 14 shows the effect of IRL1620 administration on tumor progression, stasis and regression.
  • treatment or “contributing to the treatment of include preventing, retarding the progression or growth of, shrinking, or eliminating a solid tumor. As such, these terms include both medical therapeutic and/or prophylactic administration, as appropriate.
  • container means any receptacle and closure therefor suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
  • insert means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product.
  • the package insert generally is regarded as the "label" for a pharmaceutical product.
  • An insert can come in many forms including, without limitation, a paper insert or a c.d. rom.
  • prodrug means compounds that transform rapidly in vivo to a compound useful in the invention, for example, by hydrolysis.
  • a thorough discussion of prodrugs is provided in Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14, of the A.C.S.D. Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.
  • chemotherapeutic agents have cytotoxic properties that are targeted to destroy cancer cells, but in the process inflict considerable damage to the body's normal physiological systems. It would be of great advantage, therefore, to selectively deliver chemotherapeutic agents to solid tumors thus helping to avoid these negative effects of cancer treatment.
  • the angioarchitecture of tumor blood vessels is different from that of normal blood vessels. Carmeliet & Jain, Nature, 407:249 (2000). Therefore, the vascular reactivity of tumors differs from that of normal tissue.
  • the administration of nitric oxide donors, nicotinamide and bradykinin agonists modulate blood flow to tumors. Jordan et al., lnt J Radiat Oncol Biol Phys, 48:565 (2000); Fukumura et al., Am J Pathol, 150:713 (1997); Hirst et al., Br J Radiol, 67: 795 (1994).
  • Endothelin is a vasoactive substance that modulates blood flow and is present in large concentrations in breast carcinoma tissues compared to normal breast tissue (specifically, endothelin can be present in an amount of about 12 pg/mg in breast carcinoma tissues as compared to about 0.12 pg/mg in normal breast tissue).
  • Endothelins are a family of cyclic peptides with 21 amino acids, comprising three isoforms in mammals, ET-1 , ET-2 and ET-3.
  • Endothelins exert their effects by binding to two distinct cell surface receptors, ET A and ET 6 .
  • the ET 5 receptor binds the three peptide isotypes with equal affinity.
  • the ET A receptor binds ET-1 with higher affinity than the other isoforms. Both receptors belong to the G protein-coupled receptor system and mediate biological responses from a variety of stimuli, including growth factors, vasoactive polypeptides, neurotransmitters and hormones. Masaki, J Cardiovasc Pharmacol, 35:S3 (2000); Gulati, Preface.
  • ETB receptors a focus of the present invention, are present on both endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) and are increased in breast cancer tissue (including in invasive as well as in ductal and lobular breast carcinoma tissue in humans) when compared to normal breast tissue. Wulfing et al., Oncol Rep, 11 :791 (2004); Wulfing et al., Clin Cancer Res, 9:4125 (2003); Alanen ef al., Histopathology, 36(2):161 (2000).
  • Endothelin acts on ET 5 receptors to produce vascular dilation and increase blood flow to breast tumor tissue.
  • ET B receptors predominating on ECs, produce vasodilatation via the release of factors such as prostacyclin and nitric oxide, de Nucci et al., Proc Natl Acad Sci USA, 85:9797 (1988).
  • an ETB receptor agonist can be used to selectively increase blood supply to tumors, thus increasing the targeted delivery and resulting efficacy of chemotherapeutic agents.
  • ETB receptors have been shown in, for example and without limitation, ovarian cancers, myofibroblasts, Kaposi's sarcoma tumor and intratumoral vessels, breast cancers and melanomas. Bagnato ef al., Am J Pathol, 158:841 (2001); Alanen et al., Histopathology, 36(2):161 (2000); Bagnato et al., Cancer Res, 59:720 (1999); Kikuchi ef al., Biochem Biophys Res Comm, 219:734 (1996).
  • an ET B receptor agonist in combination with a chemotherapeutic agent can be used to contribute to the treatment of solid tumors, including, without limitation, ovarian cancer, colon carcinoma, Kapoli's sarcoma, breast cancer, and melanomas.
  • ETB agonists useful in accordance with the present invention include, without limitation, ET-1, ET-2, ET-3, BQ3020, IRL1620 (N-SUC-[GIu 9 , Ala 11l15 ]ET-1 (8-21)), sarafotoxin 5 ⁇ c, [Ala 1> 3> 11> 15 JET-I, and mixtures thereof.
  • 15 ]ET-1 is a linear analog of ET-1 in which the disulfide bridges have been removed by substitution of Ala for Cys residues. Saeki et al., Biochem Biophys Res Commun, 179:286 (1991).
  • IRL1620 are truncated linear synthetic analogs of ET-1 and are the most widely used selective synthetic agonists.
  • IRL1620 is a linear ET- analog whose structure is based on the carboxy terminal end of ET-1 and has 120,000 fold selectivity for the ETB receptors.
  • IRL1620 is a highly selective and potent ETB agonist, with evidence being reported of its selectivity for the ETBI receptor subtype in preference over the ET B2 subtype. Brooks et al., J Cardiovasc Pharmacol, 26 Suppl 3:S322 (1995).
  • Chemotherapeutic agents useful in accordance with the present invention include, for example and without limitation, alkylating agents, antimetabolites, hormones and antagonists thereof, radioisotopes, antibodies, as well as natural products, and mixtures thereof.
  • an ETB agonist can be administered with antibiotics, such as doxorubicin and other anthracycline analogs, nitrogen mustards, such as, without limitation, cyclophosphamide, pyrimidine analogs such as, without limitation, 5-fluorouracil, cisplatin, hydroxyurea, and its natural and synthetic derivatives, and the like.
  • the ET 6 agonist can be administered in conjunction with, without limitation, leuprolide or goserelin (synthetic peptide analogs of LH-RH).
  • chemotherapeutic agents that can be used with the present invention include adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin, doxorubicin, interferon (alpha, beta, and/or gamma), interleukin 2, irinotecan, docetaxel, paclitaxel, topotecan, and therapeutically effective analogs and derivatives of the same.
  • an endothelin agonist is used in conjunction with a chemotherapeutic agent to contribute to the treatment of a solid tumor.
  • the endothelin agonist notably an ET B agonist
  • the ET 6 agonist therefore, provides a more selective target for the chemotherapeutic agent and improves the chemotherapeutic effect of the agent.
  • endothelin agonists stimulate ETB receptors to dilate tumor blood vessels, thereby increasing blood flow and the resultant delivery of chemotherapeutic agents to the tumor.
  • the increased blood perfusion of tumors caused by endothelin agonists also increases oxygenation of the tissue. Improved oxygenation can enhance the therapeutic action of chemotherapeutic agents.
  • Endothelin also can have mitogenic properties. The mitogenic actions of endothelin can help increase the action of chemotherapeutic agents, when administered together.
  • the mitogenic action of an endothelin agonist can increase the action of chemotherapeutic agents by improving their incorporation into dividing cells, thus increasing their efficacy.
  • Chemotherapy is frequently indicated as an adjuvant to surgery in the treatment of a cancer.
  • the goal of chemotherapy in the adjuvant setting is to reduce the risk of recurrence and enhance disease-free survival when the primary tumor has been controlled.
  • Chemotherapy is utilized as a treatment adjuvant for a cancer, frequently when the disease is metastatic.
  • An ETB agonist therefore, is particularly useful before or following surgery in the treatment of a solid tumor in combination with chemotherapy.
  • Chemically induced rat mammary carcinogenesis typically is achieved by administration of 7,12-dimethylbenzene(a)anthracene (DMBA) or N- methylnitrosourea (MNU).
  • DMBA 7,12-dimethylbenzene(a)anthracene
  • MNU N- methylnitrosourea
  • DMBA 7,12-dimethylbenzene(a)anthracene
  • MNU N- methylnitrosourea
  • breast tumors can be benign with fibroadenomas and papillomas, or they can be malignant, van Zwieten, The rat as animal model in breast cancer research. Martinus Nijhoff Publishers, Boston, pg. 206 (1984). Rats have six pairs of mammary glands, one in the cervical region, two in the thoracic region, one in the abdominal region, and two in the ingual region. Id.; Astwood et al., Am J Anat, 61 (1937). Virgin rats treated with MNU develop more tumors in the thoracic region than the abdominal region. Russo et al., Lab Invest, 57:112 (1987).
  • mice Female Sprague Dawley rats (Harlan Co., Madison, Wis.) weighing 180- 200 grams (g) were used. All animals were housed, three to a cage, in a temperature controlled room (23 ⁇ 1 °C), humidity (50 ⁇ 10%), and artificial light (0600-1800 hr). The animals were given food and water ad libitum. The experiments were conducted after the animals had been acclimatized to the environment for at least four days.
  • N-methylnitrosourea (MNU) was purchased from Ash Stevens Inc. (Detroit, Mich). IRL1620 and Endothelin-1 (ET-1) were obtained from American Peptide Company Inc. (Sunnyvale, Calif). ET-1 was dissolved in 0.1% albumin.
  • MNU 50 mg/kg or saline (1 ml/kg) was administered intraperitoneally (i.p.) to the female Sprague Dawley rats. After tumors reached 2-4 cm in diameter, blood flow experiments were performed. [0057] Rats were anesthetized with urethane (1.5 g/kg, i.p.) (Sigma Chemicals, St. Louis, Mo.), and the left femoral vein was cannulated (PE 50 tubing, Clay Adams, Parsipanny, NJ.) for drug administration.
  • urethane 1.5 g/kg, i.p.
  • Example 2 Effect of ET-1 infusion on systemic hemodynamics and blood flow to the mammary tissue of normal and tumor-bearing rats.
  • MNU and saline treatments were performed as i.p. injections three months prior to the study. Rats were palpated regularly starting four weeks after the treatments. Once tumors reached 4-8 mm in diameter, the experiments were initiated.
  • Rats were anesthetized with urethane (1.5 g/kg, i.p.) (Sigma Chemicals, St. Louis, Mo.). All surgical areas were shaved and cleaned with alcohol swabs.
  • the left femoral vein was cannulated (PE 50 tubing, Clay Adams, Parsipanny, N.J.) for drug administration.
  • the left femoral artery was cannulated (PE 50 tubing) and was used for withdrawal of reference blood sample in microsphere studies using a withdrawal pump (Model 22, Harvard Apparatus, South Natick, Mass.).
  • the right femoral artery was cannulated (PE 50 tubing) and connected to a Gould P23 ID pressure transducer for recording the blood pressure on a Grass P7D polygraph (Grass Instrument Co., Quincy, Mass., USA) through a 7Pl preamplifier.
  • the heart rate (HR) was recorded through a 7P4B Grass tachograph (Grass Instrument Co., Quincy, Mass.) triggered from blood pressure signals.
  • the right carotid artery was exposed and a PE 50 tubing was guided through the common carotid artery into the left ventricle.
  • Rats were initially divided into two groups, each receiving one of the following treatments:
  • BQ788 (N-cis2,6-dimethylpiperidinocarbonyl-L-gamma-methyll- eucyl-D-1- methoxycarbonyltrptophanyl-D-Nle);obtained from American Peptide Company Inc.
  • cardiac output (CO) ((radioactivity injected x withdrawal rate of arterial blood)/radioactivity in sampled arterial blood)
  • stroke volume (SV) (CO/HR)
  • total peripheral resistance (TPR) (mean arterial pressure (MAP)/CO)
  • MAP mean arterial pressure
  • MAP/regional blood flow The data were calculated using computer programs described in the literature. Saxena et al., Comput Programs Biomed, 12:63 (1980).
  • the lambeau was placed in a metal holder and taped down to prevent movement, then connected to a Periflux PF2b 4000 Laser Doppler Flowmetry (Perimed KB, Sweden). The time constant was set at 1.5 seconds and the bandwidth was set at 4 KHz. Data were analyzed using analysis of variance followed by Duncan's test. A level of p ⁇ 0.05 was considered significant.
  • FIGS. 4A-4C show the changes in perfusion, concentration of moving blood cells (CMBC), and velocity of red blood cells (RBC) in the breast tissue of tumor-bearing and normal rats.
  • CMBC moving blood cells
  • RBC red blood cells
  • CMBC in tumor-bearing rats increased significantly (54%; p ⁇ 0.05) at 60 minutes post ET-1 administration as compared to normal rats.
  • CMBC returned to baseline at 120 minutes after ET-1 administration.
  • the velocity of RBC increased significantly (252%; p ⁇ 0.05) at 30 minutes post ET-1 administration compared to normal rats.
  • FIGS. 5A-5C show the effect of BQ788 on changes induced by ET-1 in blood perfusion, CMBC, and velocity of RBC in tumor-bearing and normal rats, respectively.
  • Blood perfusion in the breast tissue of normal rats did not change significantly after BQ788 administration or ET-1 infusion.
  • perfusion in the breast tumor tissue of tumor-bearing rats decreased significantly at 30 (25.25.+- .5.7%; PO.05) and 60 minutes (25.17.+-.2.8%; P ⁇ 0.05) following ET-1 infusion in BQ788 pretreated rats.
  • Pretreatment with BQ788 attenuated the increase in perfusion induced by ET-1 in tumor-bearing rats. No difference between the perfusion in breast tissue of tumor-bearing rats and normal rats was observed following ET-1 administration in BQ788 pretreated rats.
  • CMBC in tumor-bearing rats was significantly higher than the baseline CMBC of breast tissue of normal rats (42.4%; P ⁇ 0.05).
  • BQ788 infusion no difference between CMBC of tumor-bearing and normal rats was observed.
  • velocity of RBC between the two groups was observed (FIGS. 5A-5C).
  • ET-1 is increased in many cancer tissues like breast carcinoma (Yamashita et al., Res Commun Chem Pathol Pharmacol, 74:363 (1991)), breast phyllode tumor (Yamashita et al., Cancer Res, 52:4046 (1992)), prostate carcinoma (Nelson et a/., Cancer Res, 56:663 (1996)), liver carcinoma (Kar et a/., Biochem Biophys Res Commun 216:514 (1995)), and some meningiomas (Pagotto et al., J Clin Invest, 96:2017 (1995)).
  • the above tests demonstrate changes in ET- 1- induced vascular responses in the breast tumor.
  • ET-1 and ET B receptor expression are augmented in breast cancer tissue. Alanen et al., Histopathology, 36:161 (2000); Yamashita et al., Res Commun Chem Pathol Pharmacol, 74:363 (1991). In accordance with the present invention, it was found that administration of BQ788 blocked the ET-1 -induced increase in blood flow to the tumor tissue.
  • BQ788 (i.e., N-cis-2,6- dimethylpiperidinocarbonyl-L-gamma-methyll- eucyl-D-1 - methoxycarbonyltrptophanyl-D-Nle) is a specific ETB receptor antagonist. BQ788 inhibits binding to ET 6 receptors with an IC 50 value of 1.2 nM.
  • BQ788 was used to determine the role of ETB receptors in ET-1 induced vasodilation in the breast tumor. This result suggests that ET-1 -induced vasodilatory responses are mediated through ETB receptors. Expression of ETB receptors is significantly higher in the endothelial cells than in the smooth muscle cells, and is regulated by various growth factors and cytokines. Smith et al., J Cardiovasc Pharmacol, 31 :S158 (1998).
  • ET 6 normal breast tissue has a higher level of ET 6 than ET A receptors (Alanen et al,, Histopathology, 36:161 (2000)), and it is theorized, but not relied upon, that during breast cancer, ET 8 receptors are overexpressed and contribute to maintaining blood flow to the tumor tissue.
  • Example 3 Effect of IRL1620 on Tumor Blood Perfusion and Chemotherapeutic Agent Delivery
  • Previous experiments demonstrated that administration of ET-1 to breast tumor bearing rats increased blood flow selectively to tumor tissue by stimulating ETB receptors.
  • the experiment described in this example will be conducted to determine the effect of the ETB receptor agonist, IRL1620 on breast and melanoma tumor perfusion and its effect on paclitaxel accumulation in tumor and other major organs.
  • nude mice will be subcutaneously inoculated with one million human melanoma cells (UISO-MEL-2). Mice with tumor volume of 300-400mm 3 will be treated with saline or IRL1620 as described previously and perfusion will be measured for 3h as described previously. Experiments will also be performed to determine whether elevated perfusion increases the accumulation of paclitaxel in tumor tissue.
  • [ 3 H]-paclitaxel (10 ⁇ Ci/mice) will be administered to melanoma bearing mice 15 min after IRL1620 or saline. Animals will be sacrificed 3h after [ 3 H]-paclitaxel administration.
  • IRL1620 will significantly increase tumor perfusion in breast tumor bearing rats and melanoma bearing mice. IRL1620 administration will result in a 150% and 318% increase in tumor perfusion in breast and melanoma bearing animals, respectively. There will be a 730% increase in tumor paclitaxel concentration in mice treated with IRL1620 compared to saline treated mice. However, IRL1620 will not significantly enhance paclitaxel concentration in other major organs. The results will show those depicted in FIG. 6.
  • IRL1620 a selective ETB receptor agonist, alters the pharmacokinetics of paclitaxel in breast tumor bearing rats.
  • IRL1620 was purchased from Sigma-Aldrich (St. Louis, MO). Paclitaxel (6 mg/mL solution) was purchased from Ben Venue Laboratories Inc. (Bedford OH). Ketamine and xylazine were purchased from Phoenix Scientific, Inc. (St. Joseph, MO). [ 3 H]-paclitaxel (ImCi, 6.4 Ci/mmol, specific activity) was purchased from Moravek Biochemicals (Moravek Biochemicals, CA). Urethane was purchased from Sigma Aldrich (Sigma Chemicals, St. Louis, MO).
  • Plasma samples were analyzed for paclitaxel using a HPLC system. Briefly, plasma was thawed and mixed with 50 ⁇ L of the internal standard N- cyclohexyl benzamide (3 mM, lower standard curve and 30 mM, higher standard curve) and 3mL of ethyl ether (Fisher Scientific, Chicago, IL) in a 13 x 100 glass culture tube. The mixture was shaken using a reciprocal shaker for 5 minutes and then centrifuged for 5 minutes at 3,000 rpm at 4 0 C. The resulting supernatant was transferred to a 13 x 100 borosilicate glass culture tube and evaporated under a stream of nitrogen in a heated water bath (37°C).
  • the internal standard N- cyclohexyl benzamide 3 mM, lower standard curve and 30 mM, higher standard curve
  • ethyl ether Fethyl ether
  • the residue was reconstituted with 200 ⁇ L of mobile phase A (50% deionized water, 50% acetonitrile).
  • a 100 ⁇ L (lower standard curve and samples collected after IV administration) aliquot of the reconstituted material was injected into a 4mm NovaPak 150 x 3.9mm C18 column (Waters Associates, Milford, MA) preceded by a 4mm NovaPak 20 x 3.9mm C18 precolumn using a Waters 2695 separations module connected to a Waters 2487 absorbance detector set at 227 nm.
  • a linear gradient was started with 100% mobile phase A pumped at a flow rate of 1 mL/min.
  • Plasma concentrations for paclitaxel were calculated from the ratio of the area of the paclitaxel peak to the area of the N-cyclohexyl benzamide peak using least-squares linear regression and weighting by 1/x. Within day and between days variability measured by a coefficient of variation was ⁇ 10%. Plasma concentration profiles of normal and tumor bearing rats were compared.
  • IRL1620 was administered to tumor bearing animals at a dose of 3nmol/kg, i.v. [ 3 H]-paclitaxel (160 ⁇ Ci/kg) was mixed with unlabeled paclitaxel. Paclitaxel was administered i.v. 15 minutes following vehicle or IRL1620 administration.
  • fmol/mL dpm value x decay factor x 2.2x10 '12 / 10 ⁇ 12 x volume of sample in mL
  • the pharmacokinetics of the total paclitaxel was calculated using the ratio of [ 3 H]-paclitaxel to unlabeled paclitaxel.
  • Plasma paclitaxel pharmacokinetic estimates were determined using both non- compartmental and compartmental analyses as implemented in WinNonlin Pro 4.I (Pharsight Corp, Mt. View, CA).
  • the area under the curve (AUCO- 00 ) was estimated using the trapezoidal rule to the last measurable concentration (Clast) and extrapolated to infinity by dividing Clast by the negative value of the terminal slope ( ⁇ ) of the log-linear plasma concentration vs. time curve.
  • the following parameters were also calculated: mean residence time (MRTiv) was calculated as the reciprocal of systemic clearance (CL) was calculated as the ratio of dose to AUCO- 00 and apparent volume distribution was calculated the ratio of CL and ⁇ .
  • Plasma half-life was calculated as the product of 0.693 (natural log 2) and MRTiv.
  • compartmental analyses a series of non-linear compartmental models were fitted to the plasma concentration vs. time curve data. Specifically, one-compartmental, two-compartmental and three-compartmental models were compared. Uniform and Predicted data based weighting were tested. The final selection of the model was based on diagnostic plots (observed vs. predicted and plot of residuals), Akaike Information Criteria (AIG) and Schwartz Criteria (SC). The model with a lower AIC and SC criteria was considered the final model.
  • AIG Akaike Information Criteria
  • SC Schwartz Criteria
  • FIG. 7 The pharmacokinetic profile of paclitaxel was not affected by IRL1620 administration (FIGS. 7 and 8) in normal and tumor bearing rats. HPLC analysis of the plasma pharmacokinetic profile is similar to the more extensive profile of radioactive paclitaxel disposition.
  • Figure 8 depicts the pharmacokinetic profile of paclitaxel radioactivity in vehicle treated and IRL1620 treated tumor bearing rats. The pharmacokinetic profile was analyzed by noncompartmental and compartmental methods.
  • the AUC calculated for the vehicle + paclitaxel group was 9433.53 ⁇ 1465.00 ng*h/mL and was similar (p > 0.05) to that of IRL1620 treated tumor rats.
  • the elimination half-life was calculated as 0.14 + 0.08 hr.
  • the clearance calculated as Dose/AUC was estimated to be 0.56 ⁇ 0.07 L/h/kg.
  • the volume of distribution, calculated as clearance/Kel was found to be 10.11 ⁇ 4.17 L/kg.
  • IRL1620 did not affect the pharmacokinetic profile of paclitaxel.
  • ⁇ t 1 / 2 , ⁇ V ⁇ Y V ⁇ were 0.03 ⁇ 0.01 h, 1.0 ⁇ 0.32 h, and 25.87 + 17.81 h, respectively.
  • the mean residence time was 27.92 ⁇ 19.84 h.
  • IRL1620 did not affect the pharmacokinetics of paclitaxel. Often pharmacokinetics can be considered as a surrogate for safety of the compound. Hence these results also suggest that the safety of paclitaxel does not change due to the administration of IRL1620. As a result, IRL1620 could be used to improve paclitaxel efficacy and allow for appropriate dose titration to minimize its severe toxicities. These results show that the pharmacokinetic profile of paclitaxel in normal rats was similar to tumor bearing rats indicating that paclitaxel disposition is not altered by the tumor model system.
  • Example 5 Dose Response Effect of IRL 1620, Effect of IRL 1620 on the Bio- Distribution of [ 3 H] paclitaxel in Major Organs and Tumor Tissue and Effect of IRL1620 on Efficacy of Paclitaxel on Tumor Status
  • the experiments described in the present example were designed to determine (a) the dose response effect of ETB receptor agonist, IRL1620, on breast perfusion of normal and tumor bearing rats, (b) the effect of IRL1620 on the bio- distribution of [ 3 H] paciitaxel in major organs and tumor tissue and (3) the effect of 1RL1620 on the efficacy of paciitaxel on tumor status in MNU-induced breast tumor bearing rats.
  • IRL1620 was obtained from Sigma Chemical Co. (St. Louis, MO).
  • [ 3 H] paciitaxel was purchased from Moravek Biochemicals (Brea, CA). Paciitaxel (6 mg/ml solution) was purchased from Ben Venue Laboratories Inc. (Bedford, OH). Ketamine and xylazine were purchased from Phoenix Scientific, Inc. (St. Joseph, MO). Tissue solubilizer (TS-2) was purchased from RPI Corp. (Chicago, IL).
  • Perfusion study Perfusion to the rat mammary tissue and tumor was measured using a Periflux PF2b 4000 Laser Doppler Flowmetry (Perimed, Sweden) as previously described. Briefly, rats were anesthetized using ketamine (100 mg/kg) and xylazine (2 mg/kg) as a combined single i.p injection. The fur was shaved around the nipples and the animals were placed on a heating pad (37 0 C) to minimize temperature variations. The skin surrounding the mammary glands was dissected out about 6 mm wide and about 4 mm long. A standard model fiber optic probe (MP3 flow probe, Moors Instruments, Devon, England) was applied to the surface of the exposed tissue.
  • MP3 flow probe Moors Instruments, Devon, England
  • the contents of the vial were equally divided into 3 vials and 15 ml of liquid scintillation cocktail (Safety Solve, RPI Corp, Chicago, IL) was added to each vial and kept overnight for equilibration. The radioactivity in the tubes was counted using a liquid scintillation counter (Beckman Coulter, LS 6500).
  • liquid scintillation cocktail Safety Solve, RPI Corp, Chicago, IL
  • Body weight, tumor size and location were monitored on every third day for a total of 30 days after the final dose.
  • the following categories were used for the scoring. Progression: the tumor grows more than 40% in area compared to commencement of treatment; Stasis: the tumor did not fluctuate more than 40% from its initial area throughout the course of treatment; Partial regression: the tumor regressed more than 40% from its initial area; Complete remission: where the tumor is no longer palpable and measurable: Tumor multiplicity (appearance of new tumors) during the treatment and 30 day observation period was also recorded. The animals were sacrificed 30 days after the final (5th) dose. Data were analyzed using analysis of variance followed by Duncan's test. A level of P ⁇ 0.05 was considered significant.
  • FIG. 10A Dose response of IRL1620 on breast perfusion.
  • the effect of IRL1620 administration on tumor perfusion was found to be transient and dose related (FIG. 10A).
  • a maximum increase of 244.0% (p ⁇ 0.001) from the baseline in tumor perfusion was observed at 15 min after the administration of 3 nmol/kg of IRL1620.
  • the increase in perfusion was found to be significant at 15, 30 and 60 minutes compared to baseline as well as saline treated rats.
  • FIG. 10B Administration of 1 and 9 nmol/kg of IRL1620 produce only marginal increases in breast tumor perfusion compared to the baseline perfusion and that of saline treated rats.
  • Efficacy study Tumor volume. Tumor sizes in various groups were comparable and not significantly different from each other at the commencement of treatment (FIG. 13).
  • the tumor volume of control rats increased at a rapid and variable rate. Large variability in tumor growth may be attributed to the random growth pattern of autochthonously growing tumors.
  • the control tumors had a tumor volume of 2693.4 ⁇ 790.9 mm 3 .
  • IRL1620 treated rats had a similar pattern of development with a final tumor volume of 2560.5 ⁇ 844.4 mm 3 . Cremophor ELEthanol treatment also resulted in a similar growth pattern with a final tumor volume of 2338 ⁇ 1329 mm 3 .
  • IRL1620 and cremophor El.ethanol did not have a significant effect on the growth of MNU-induced breast tumors.
  • Vehicle + paclitaxel 1 mg/kg treated rats showed a slightly reduced growth in tumor size (1960.8 ⁇ 611.9 mm 3 ) which was more pronounced in the vehicle + paclitaxel 5 mg/kg group (1682.7 ⁇ 497.3 mm 3 ) when compared to control rats.
  • IRL1620 + paclitaxel 1 mg/kg treated rats showed reduced tumor size (1707.2 ⁇ 621.1 mm 3 ). However, the lowest average tumor size (730.1 ⁇ 219.4 mm 3 ) was observed in the group of animals treated with IRL1620 + paclitaxel 5 mg/kg (FIG. 13).
  • Efficacy study Tumor multiplicity. Animals in all treatment groups developed additional tumors by the end of 30 day observation period. There was a 58.4, 57.1 and 60.8% increase in additional tumor appearance in animals treated with saline, cremophor EL:ethanol and IRL1620, respectively. New tumor occurrence was found to be 78.3 and 41% in animals administered with vehicle + paclitaxel 1 and 5 mg/kg, respectively. However, percent of additional tumors was found to be 69.2 and 44.8% in IRL1620 + paclitaxel 1 and 5 mg/kg, respectively.
  • Efficacy study Tumor regression.
  • Administration of IRL1620 prior to paclitaxel 5 mg/kg treatment significantly reduced the progression of tumors compared to control animals.
  • the saline treated rats showed a 9.2% of tumors regressing from the initial tumor volume.
  • Cremophor ELethanol (4.3%), IRL1620 (3.4%) and vehicle + paclitaxel (5 mg/kg) (9.5%) treated rats were not significantly different from the control group in the percent of tumors regressing in size.
  • tumors had regressed by 76.1 ⁇ 10.5 and 45.9 ⁇ 11.5% in the IRL1620 + paclitaxel 5 mg/kg treated rats and vehicle + paclitaxel 5 mg/kg treated rats, respectively compared to control rats.
  • the tumor regression rate in IRL1620 + paclitaxel 1 mg/kg and vehicle + paclitaxel (1 mg/kg) group was found to be 47.1 + 15.4 and 37..7 ⁇ 16.2%, respectively.
  • IRL1620 can be used as a tumor-selective vasodilator and can be used to selectively increase the efficacy of chemotherapy.
  • the present study clearly demonstrates that multi-fold higher drug concentrations can be achieved in the tumor tissue by adopting this therapeutic strategy.
  • ET A receptor antagonists have also been proposed to improve tumor blood flow (Sonveaux et a/., Cancer Res, 64:3209 (2004)) and can be used to enhance delivery of anticancer drugs to the tumor in accordance with the present invention.
  • compositions containing the active ingredients are suitable for administration to humans or other mammals.
  • the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered.
  • Administration of the pharmaceutical composition can be performed before, during, or after the onset of solid tumor growth.
  • a method of the present invention can be accomplished using active ingredients as described above, or as a physiologically acceptable salt, derivative, prodrug, or solvate thereof.
  • the active ingredients can be administered as the neat compound, or as a pharmaceutical composition containing either or both entities.
  • compositions include those wherein the active ingredients are administered in an effective amount to achieve their intended purpose. More specifically, a “therapeutically effective amount” means an amount effective to prevent development of, to eliminate, to retard the progression of, or to reduce the size of a solid tumor. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a "therapeutically effective dose” refers to that amount of the active ingredients that results in achieving the desired effect. Toxicity and therapeutic efficacy of such active ingredients can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD 50 and ED 5 O- A high therapeutic index is preferred. The data obtained can be used in formulating a range of dosage for use in humans. The dosage of the active ingredients preferably lies within a range of circulating concentrations that include the ED 50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized.
  • composition and dosage is determined by an individual physician in view of the patient's condition. Dosage amount and interval can be adjusted individually to provide levels of the active ingredients that are sufficient to maintain therapeutic or prophylactic effects.
  • the amount of pharmaceutical composition administered can be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.
  • compositions for use in accordance with the present invention thus can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active ingredients into preparations which can be used pharmaceutically.
  • the composition can be in the form of a pyrogen-free, parenterally acceptable aqueous solution.
  • parenterally acceptable solutions having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred composition for intravenous injection typically will contain an isotonic vehicle although this characteristic is not required.
  • the active ingredients are administered as a suitably acceptable formulation in accordance with normal veterinary practice.
  • the veterinarian can readily determine the dosing regimen that is most appropriate for a particular animal.
  • Various adaptations and modifications of the embodiments can be made and used without departing from the scope and spirit of the present invention which can be practiced other than as specifically described herein.
  • the above description is intended to be illustrative, and not restrictive.
  • the scope of the present invention is to be determined only by the claims.

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Abstract

L'invention concerne des méthodes, des compositions et des articles manufacturés destinés à contribuer au traitement de tumeurs cancéreuses solides. Lesdites méthodes, compositions et lesdits articles manufacturés peuvent faire appel à un agoniste de l'endothéline B (ETB) pour améliorer l'administration d'un agent chimiothérapeutique dans une tumeur solide chez des mammifères, y compris des être humains.
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US8026216B2 (en) 2002-10-24 2011-09-27 Spectrum Pharmaceuticals, Inc. Methods and compositions for contributing to the treatment of cancers
US20070032422A1 (en) 2002-10-24 2007-02-08 Spectrum Pharmaceuticals, Inc. Methods, compositions and articles of manufacture for contributing to the treatment of cancers
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