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Anti-Cancer Activities and Interaction of Imiquimod and Flex-Het, SHetA2, in Melanoma and Ovarian Cancer

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DOI: 10.4236/jct.2013.46A1002    4,369 Downloads   6,282 Views   Citations

ABSTRACT

New strategies are needed to treat cancers that do not respond to chemotherapy or resist chemotherapy after responding initially. The objective of this study was to evaluate non-cytotoxic drugs against two of these cancers, melanoma and ovarian cancer. Imiquimod is an immune stimulant that induces apoptosis in cancer cells. Flexible-Heteroarotinoids (Flex-Hets) are small molecules that regulate growth, differentiation and apoptosis in cancer cells with reduced effects on normal cells. Both imiquimod and SHetA2 inhibited growth and induced apoptosis in the B16 melanoma cell line and cisplatin-sensitive A2780 and cisplatin-resistant OVCAR-3 ovarian cancer cell lines. The growth inhibition was additive in A2780 and B16, and synergistic in OVCAR-3. Both compounds inhibited endothelial tube branching in vitro and exerted an additive effect when combined. Various combinations of imiquimod and SHetA2 did not cause significant differences in the overall survival in the syngeneic B16 murine melanoma model. SHetA2 induced complete tumor regression and a melanoma-free natural life-span in two mice. These cures occurred in one of ten mice treated with oral SHetA2 and one of ten mice intratumorally-injected with SHetA2. Exploratory modeling of the distribution of survival times suggested that the two surviving mice represent rare events. Histologic evaluation of the tumors revealed that imiquimod induced necrosis, SHetA2 induced differentiated architecture and increased cytoplasm, both agents reduced mitotic indices and angiogenesis and neither agent counteracted the effects of the other. No overt toxicities were observed. In conclusion, imiquimod and SHetA2 exhibit complementary anti-cancer activity in vitro and SHetA2 has promise as a single agent.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

M. Naylor, D. Thompson, S. Lightfoot and D. Benbrook, "Anti-Cancer Activities and Interaction of Imiquimod and Flex-Het, SHetA2, in Melanoma and Ovarian Cancer," Journal of Cancer Therapy, Vol. 4 No. 6A, 2013, pp. 7-19. doi: 10.4236/jct.2013.46A1002.

References

[1] M. A. Cheever, J. Schlom, L. M. Weiner, H. K. Lyerly, M. L. Disis, A. Greenwood, O. Grad, W. G. Nelson and Translational Research Working, “Translational Research Working Group Developmental Pathway for Immune Response Modifiers,” Clinical Cancer Research, Vol. 14, No. 18, 2008, pp. 25692-25699. doi:10.1158/1078-0432.CCR-08-1266
[2] S. A. Rosenberg and M. E. Dudley, “Adoptive Cell Therapy for the Treatment of Patients with Metastatic Melanoma,” Current Opinion in Immunology, Vol. 21, No. 2, 2009, pp. 233-240. doi:10.1016/j.coi.2009.03.002
[3] L. E. Kandalaft, D. J. Powell, N. Singh and G. Coukos, “Immunotherapy for Ovarian Cancer: What’s Next?” Journal of Clinical Oncology, Vol. 29, No. 7, 2011, pp. 925-933. doi:10.1200/JCO.2009.27.2369
[4] M. B. Lens and M. Dawes, “Global Perspectives of Contemporary Epidemiological Trends of Cutaneous Malignant Melanoma,” British Journal of Dermatology, Vol. 150, No. 2, 2004, pp. 179-185. doi:10.1111/j.1365-2133.2004.05708.x
[5] M. S. Evans, S. V. Madhunapantula, G. P. Robertson and J. J. Drabick, “Current and Future Trials of Targeted Therapies in Cutaneous Melanoma,” Advances in Experimental Medicine & Biology, Vol. 779, 2013, pp. 223-255. doi:10.1007/978-1-4614-6176-0_10
[6] G. Bollag, P. Hirth, J. Tsai, J. Zhang, P. N. Ibrahim, H. Cho, W. Spevak, C. Zhang, Y. Zhang, G. Habets, E. A. Burton, B. Wong, G. Tsang, B. L. West, B. Powell, R. Shellooe, A. Marimuthu, H. Nguyen, K. Y. J. Zhang, D. R. Artis, J. Schlessinger, F. Su, B. Higgins, R. Iyer, K. D/’Andrea, A. Koehler, M. Stumm, P. S. Lin, R. J. Lee, J. Grippo, I. Puzanov, K. B. Kim, A. Ribas, G. A. McArthur, J. A. Sosman, P. B. Chapman, K. T. Flaherty, X. Xu, K. L. Nathanson and K. Nolop, “Clinical Efficacy of a RAF Inhibitor Needs Broad Target Blockade in BRAF-Mutant Melanoma,” Nature, Vol. 467, No. 7315, 2010, pp. 596-599. doi:10.1038/nature09454
[7] S. L. Topalian, F. S. Hodi, J. R. Brahmer, S. N. Gettinger, D. C. Smith, D. F. McDermott, J. D. Powderly, R. D. Carvajal, J. A. Sosman, M. B. Atkins, P. D. Leming, D. R. Spigel, S. J. Antonia, L. Horn, C. G. Drake, D. M. Pardoll, L. Chen, W. H. Sharfman, R. A. Anders, J. M. Taube, T. L. McMiller, H. Xu, A. J. Korman, M. Jure-Kunkel, S. Agrawal, D. McDonald, G. D. Kollia, A. Gupta, J. M. Wigginton and M. Sznol, “Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer,” New England Journal of Medicine, Vol. 366, No. 26, 2012, pp. 2443-2454. doi:10.1056/NEJMoa1200690
[8] F. S. Hodi, S. J. O’Day, D. F. McDermott, R. W. Weber, J. A. Sosman, J. B. Haanen, R. Gonzalez, C. Robert, D. Schadendorf, J. C. Hassel, W. Akerley, A. J. M. van den Eertwegh, J. Lutzky, P. Lorigan, J. M. Vaubel, G. P. Linette, D. Hogg, C. H. Ottensmeier, C. Lebbé, C. Peschel, I. Quirt, J. I. Clark, J. D. Wolchok, J. S. Weber, J. Tian, M. J. Yellin, G. M. Nichol, A. Hoos and W. J. Urba, “Improved Survival with Ipilimumab in Patients with Metastatic Melanoma,” New England Journal of Medicine, Vol. 363, No. 8, 2010, pp. 711-723. doi:10.1056/NEJMoa1003466
[9] I. Romero and R. C. Bast Jr., “Minireview: Human Ovarian Cancer: Biology, Current Management, and Paths to Personalizing Therapy,” Endocrinology, Vol. 153, No. 4, 2012, pp. 1593-1602. doi:10.1210/en.2011-2123
[10] M. A. Bookman, M. F. Brady, W. P. McGuire, P. G. Harper, D. S. Alberts, M. Friedlander, N. Colombo, J. M. Fowler, P. A. Argenta, K. DeGeest, D. G. Mutch, R. A. Burger, A. M. Swart, E. L. Trimble, C. Accario-Winslow and L. M. Roth, “Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer Intergroup,” Journal of Clinical Oncology, Vol. 27, No. 9, 2009, pp. 1355-1358. doi:10.1200/JCO.2008.19.1684
[11] C. Hesling, M. D’Incan, S. Mansard, F. Franck, A. Corbin-Duval, C. Chevenet, P. Dechelotte, J. C. Madelmont, A. Veyre, P. Souteyrand and Y. J. Bignon, “In Vivo and in Situ Modulation of the Expression of Genes Involved in Metastasis and Angiogenesis in a Patient Treated with Topical Imiquimod for Melanoma Skin Metastases,” British Journal of Dermatology, Vol. 150, No. 4, 2004, pp. 761-767. doi:10.1111/j.0007-0963.2004.05898.x
[12] A. Steinmann, J. O. Funk, G. Schuler and P. von den Driesch, “Topical Imiquimod Treatment of a Cutaneous Melanoma Metastasis,” Journal of the American Academy of Dermatology, Vol. 43, No. 3, 2000, pp. 555-556. doi:10.1046/j.1365-2133.2002.488811.x
[13] I. H. Wolf, J. Smolle, B. Binder, L. Cerroni, E. Richtig and H. Kerl, “Topical Imiquimod in the Treatment of Metastatic Melanoma to Skin,” Archives in Dermatology, Vol. 139, No. 3, 2003, pp. 273-276. doi:10.1001/archderm.139.3.273
[14] A. B. Bong, B. Bonnekoh, I. Franke, M. P. Schon, J. Ulrich and H. Gollnick, “Imiquimod, a Topical Immune Response Modifier, in the Treatment of Cutaneous Metastases of Malignant Melanoma,” Dermatology, Vol. 205, No. 2, 2002, pp. 135-138. doi:10.1159/000063904
[15] S. Ugurel, A. Wagner, C. Pfohler, W. Tilgen and U. Reinhold, “Topical Imiquimod Eradicates Skin Metastases of Malignant Melanoma But Fails to Prevent Rapid Lymphogenous Metastatic Spread,” British Journal of Dermatology, Vol. 147, No. 3, 2002, pp. 621-624. doi:10.1046/j.1365-2133.2002.488811.x
[16] P. Vereecken, A. Mathieu, M. Laporte, M. Petein, T. Velu, A. Awada and M. Heenen, “Management of Cutaneous Locoregional Recurrences of Melanoma: A New Therapeutic Perspective with Imiquimod,” Dermatology, Vol. 206, No. 3, 2003, pp. 279-280. doi:10.1159/000068901
[17] C. Loquai, D. Nashan, D. Metze, U. Beiteke, K. W. Ruping, T. A. Luger and S. Grabbe, “Imiquimod, Pegylated Interferon-Alpha-2b and Interleukin-2 in the Treatment of Cutaneous Melanoma Metastases,” Hautarzt, Vol. 55, No. 2, 2004, pp. 176-181. doi:10.1007/s00105-003-0625-z
[18] B. Berman, V. N. Poochareon and A. M. Villa, “Novel Dermatologic Uses of the Immune Response Modifier Imiquimod 5% Cream,” Skin Therapy Letters, Vol. 7, No. 9, 2002, pp. 1-6. http://www.skintherapyletter.com/2002/7.9/1.html
[19] R. Sidbury, “What’s New in Pediatric Dermatology: Update for the Pediatrician,” Current Opinion in Pediatrics, Vol. 16, No. 4, 2004, pp. 410-414. doi:10.1097/01.mop.0000133081.24760.08
[20] M. I. Martinez, I. Sanchez-Carpintero, P. E. North and M. C. Mihm Jr., “Infantile Hemangioma: Clinical Resolution with 5% Imiquimod Cream,” Archives in Dermatology, Vol. 138, No. 7, 2002, pp. 881-884. doi:10.1001/archderm.138.7.881
[21] R. Sidbury, N. Neuschler, E. Neuschler, P. Sun, X. Q. Wang, R. Miller, M. Tomai, E. Puscasiu, S. Gugneja and A. S. Paller, “Topically Applied Imiquimod Inhibits Vascular Tumor Growth in Vivo,” Journal of Investigative Dermatology, Vol. 121, No. 5, 2003, pp. 1205-1209. doi:10.1046/j.1523-1747.2003.12521.x
[22] S. Majewski, M. Marczak, B. Mlynarczyk, B. Benninghoff and S. Jablonska, “Imiquimod Is a Strong Inhibitor of Tumor Cell-Induced Angiogenesis,” International Journal of Dermatology, Vol. 44, No. 1, 2005, pp. 14-19. doi:10.1111/j.1365-4632.2004.02318.x
[23] P. Savage, V. Horton, J. Moore, M. Owens, P. Witt and M. E. Gore, “A Phase I Clinical Trial of Imiquimod, an Oral Interferon Inducer, Administered Daily,” British Journal of Cancer, Vol. 74, No. 9, 1996, pp. 1482-1486. doi:10.1038/bjc.1996.569
[24] M. Naylor, “Verbal Communication with 3M Pharmaceuticals.”
[25] D. K. Armstrong, B. Bundy, L. Wenzel, H. Q. Huang, R. Baergen, S. Lele, L. J. Copeland, J. L. Walker, R. A. Burger and Gynecologic Oncology Group, “Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer,” New England Journal of Medicine, Vol. 354, No. 1, 2006, pp. 34-43. doi:10.1056/NEJMoa052985
[26] C. Ingves and G. B. Jemec, “Combined Imiquimod and Acitretin for Non-Surgical Treatment of Basal Cell Carcinoma,” Scandinavian Journal of Plastic Reconstructive Surgery and Hand Surgery, Vol. 37, No. 5, 2003, pp. 293-295. doi:10.1080/02844310310001724
[27] B. Giannotti, L. Vanzi, E. M. Difonzo and N. Pimpinelli, “The Treatment of Basal Cell Carcinomas in a Patient with Xeroderma Pigmentosum with a Combination of Imiquimod 5% Cream and Oral Acitretin,” Clinical and Experimental Dermatology, Vol. 28, No. 1, 2003, pp. 33-35. doi:10.1046/j.1365-2230.28.s1.11.x
[28] M. Gaboli, D. Gandini, L. Delva, Z. G. Wang and P. P. Pandolfi, “Acute Promyelocytic Leukemia as a Model for Cross-Talk between Interferon and Retinoic Acid Pathways: From Molecular Biology to Clinical Applications,” Leukemia & Lymphoma, Vol. 30, No. 1-2, 1998, pp. 11-22.
[29] G. Fierlbeck, T. Schreiner and G. Rassner, “Combination of Highly Purified Human Leukocyte Interferon and 13-cis-Retinoic Acid for the Treatment of Metastatic Melanoma,” Cancer Immunology and Immunotherapy, Vol. 40, No. 3, 1995, pp. 157-164. doi:10.1007/BF01517347
[30] A. Haque, A. Das, L. M. Hajiaghamohseni, A. Younger, N. L. Banik and S. K. Ray, “Induction of Apoptosis and Immune Response by All-Trans Retinoic Acid Plus Interferon-Gamma in Human Malignant Glioblastoma T98G and U87MG Cells,” Cancer Immunology and Immunotherapy, Vol. 56, No. 5, 2007, pp. 615-625. doi:10.1007/s00262-006-0219-6
[31] S. Vertuani, E. Dubrovska, V. Levitsky, M. J. Jager, R. Kiessling and J. Levitskaya, “Retinoic Acid Elicits Cytostatic, Cytotoxic and Immunodulatory Effects in Uveal Melanoma Cells,” Cancer Immunology and Immunotherapy, Vol. 56, No. 2, 2007, pp. 193-204. doi:10.1007/s00262-006-0185-z
[32] E. Garattini, L. Mologni, I. Ponzanelli and M. Terao, “CrossTalk between Retinoic Acid and Interferons: Molecular Mechanisms of Interaction in Acute Promyelocytic Leukemia Cells,” Leukemia & Lymphoma, Vol. 30, No. 5-6, 1998, pp. 467-475.
[33] D. V. Kalvakolanu, “The GRIMs: A New Interface between Cell Death Regulation and Interferon/Retinoid Induced Growth Suppression,” Cytokine & Growth Factor Reviews, Vol. 15, No. 2, 2004, pp. 169-194. doi:10.1016/j.cytogfr.2004.01.002
[34] F. Recchia, G. Saggio, A. Cesta, G. Candeloro, A. Di Blasio, G. Amiconi, M. Lombardo, A. Nuzzo, A. Lalli, E. Alesse, S. Nceozione and S. Rea, “Phase II Study of Interleukin-2 and 13-cis-Retinoic Acid as Mainenance Therapy in Metastatic Colorectal Cancer,” Cancer Immunology and Immunotherarpy, Vol. 56, No. 5, 2006, pp. 699-708.
[35] D. S. Alberts, O. M. Colvin, A. H. Conney, V. L. Ernster, J. E. Garber, P. Greenwald, L. Gudas, K. W. Hong, G. J. Kelloff, R. A. Kramer, C. E. Lerman, D. J. Mangelsdorf, A. Matter, J. D. Minna, W. G. Nelson, J. M. Pezzuto, F. Prendergast, V. W. Rusch, M. B. Sporn, L. W. Wattenberg and I. B. Weinstein, “Prevention of Cancer in the Next Millennium: Report of the Chemoprevention Working Group to the American Association for Cancer Research,” Cancer Research, Vol. 59, No. 19, 1999, pp. 4743-4748. http://cancerres.aacrjournals.org/content/59/19/4743.long
[36] F. R. Khuri, S. M. Lippman, M. R. Spitz, R. Lotan and W. K. Hong, “Molecular Epidemiology and Retinoid Chemoprevention of Head and Neck Cancer,” Journal of the National Cancer Institute, Vol. 89, No. 3, 1997, pp. 199-211. doi:10.1093/jnci/89.3.199
[37] G. de Palo, L. Mariani, T. Camerini, E. Marubini, F. Formelli, B. Pasini, A. Decensi and U. Veronesi, “Effect of Fenretinide on Ovarian Carcinoma Occurrence,” Gynecologic Oncology, Vol. 86, No. 1, 2002, pp. 24-27. doi:10.1006/gyno.2002.6663
[38] R. D. Alvarez, M. G. Conner, H. Weiss, P. M. Klug, S. Niwas, U. Manne, J. Bacus, V. Kagan, K. C. Sexton, C. J. Grubbs, I. E. Eltoum and W. E. Grizzle, “The Efficacy of 9-Cis-Retinoic Acid (Aliretinoin) as a Chemopreventive Agent for Cervical Dysplasia: Results of a Randomized Double-Blind Clinical Trial,” Cancer Epidemiology, Biomarkers and Prevention, Vol. 12, No. 2, 2003, pp. 114-119. http://cebp.aacrjournals.org/content/12/2/114.full.pdf+html
[39] M. Follen, E. N. Atkinson, D. Schottenfeld, A. Malpica, L. West, S. Lippman, C. Zou, W. N. Hittelman, R. Lotan and W. K. Hong, “A Randomized Clinical Trial of 4-Hydroxyphenylretinamide for High-Grade Squamous Intraepithelial Lesions of the Cervix,” Clinical Cancer Research, Vol. 7, No. 11, 2001, pp. 3356-3365. http://clincancerres.aacrjournals.org/content/7/11/3356.long
[40] R. Masetti, C. Biagi, D. Zama, F. Vendemini, A. Martoni, W. Morello, P. Gasperini and A. Pession, “Retinoids in Pediatric Onco-Hematology: The Model of Acute Promyelocytic Leukemia and Neuroblastoma,” Advances in Therapy, Vol. 29, No. 9, 2012, pp. 747-762. doi:10.1007/s12325-012-0047-3
[41] V. Duong and C. Rochette-Egly, “The Molecular Physiology of Nuclear Retinoic acid Receptors. From Health to Disease,” Biochimica et Biophysica Acta, Vol. 1812, No. 8, 2011, pp. 1023-1031. doi:10.1016/j.bbadis.2010.10.007
[42] D. M. Benbrook, “Refining Retinoids with Heteroatoms,” Minireviews in Medicinal Chemistry, Vol. 2, No. 3, 2002, pp. 271-277. doi:10.2174/1389557023406160
[43] M. I. Dawson, P. D. Hobbs, K. Derdzinski, R. L.-S. Chan, J. Gruber, W.-R. Chao, S. Smith, R. W. Thies and L. J. Schiff, “Conformationally Restricted Retinoids,” Journal of Medicinal Chemistry, Vol. 27, No. 11, 1984, pp. 1516-1531. doi:10.1021/jm00377a022
[44] C. Lindamood III, F. O. Cope, D. L. Dillehay, M. P. Everson, H. D. Giles, E. W. Lamon, D. J. McCarthy, J. L. Sartin and D. L. Hill, “Pharmacological and Toxicological Properties of Arotinoids SMR-2 and SMR-6 in Mice,” Fundamental and Applied Toxicology, Vol. 14, No. 1, 1990, pp. 15-29. doi:10.1093/toxsci/14.1.15
[45] C. I. Lindamood, D. L. Dillehay, E. W. Lamon, H. D. Giles, Y. F. Shealy, B. P. Sani and D. L. Hill, “Toxicologic and Immunologic Evaluations of N-(All-trans-Retinoyl)-DL-Leucine and N-(all-trans-Retinoyl)glycine,” Toxicolog and Applied Pharamcolology, Vol. 96, No. 2, 1988, pp. 279-295. doi:10.1016/0041-008X(88)90087-7
[46] D. M. Benbrook, M. M. Madler, L. W. Spruce, P. J. Birckbichler, E. C. Nelson, S. Subramanian, G. M. Weerasekare, J. B. Gale, M. K. Patterson Jr., B. Wang, W. Wang, S. Lu, T. C. Rowland, P. DiSilvestro, C. Lindamood III, D. L. Hill and K. D. Berlin, “Biologically Active Heteroarotinoids Exhibit Anticancer Activity and Decreased Toxicity,” Journal of Medicinal Chemistry, Vol. 40, No. 22, 1997, pp. 3567-3583. doi:10.1021/jm970196m
[47] K. M. Waugh, K. D. Berlin, W. T. Ford, E. M. Holt, J. P. Carroll, P. R. Schomber and L. J. Schiff, “Synthesis and Characterization of Selected Heteroarotinoids. Pharmacological Activity as Assessed in Vitamin a Deficient Hamster Tracheal Organ Cultures. Single Crystal X-Ray Diffraction Analysis of 4,4-Dimethylthiochroman-6-yl methyl ketone 1,1-Dioxide and Ethyl (E)-p-[2-(4,4-Dimethyl thiochroman-6-yl)Benzoate,” Journal of Medicinal Chemistry, Vol. 28, No. 1, 1985, pp. 116-124. doi:10.1021/jm00379a021
[48] R. A. S. Chandraranta, “Tazarotene-First of a New Generation of Receptor-Selective Retinoids,” British Journal of Dermatology, Vol. 135, No. S49, 1996, pp. 18-25.
[49] S. Guruswamy, S. Lightfoot, M. Gold, R. Hassan, K. D. Berlin, R. T. Ivey and D. M. Benbrook, “Effects of Retinoids on Cancerous Phenotype and Apoptosis in Organotypic Culture of Ovarian Carcinoma,” Journal of the National Cancer Institute, Vol. 93, No. 7, 2001, pp. 516-525. doi:10.1093/jnci/93.7.516
[50] S. Liu, C. W. Brown, K. D. Berlin, A. Dhar, S. B. Guruswamy, D. Brown, G. J. Gardner, M. J. Birrer and D. M. Benbrook, “Synthesis of Flexible Sulfur-Containing Heteroarotinoids that Induce Apoptosis and Reactive Oxygen Species with Discrimination between Malignant and Benign Cells,” Journal of Medicinal Chemistry, Vol. 47, No. 4, 2004, pp. 999-1007. doi:10.1021/jm030346v
[51] D. M. Benbrook, S. A. Kamelle, S. B. Guruswamy, S. A. Lightfoot, B. Hannafon, T. L. Rutledge, N. S. Gould, S. T. Dunn and K. D. Berlin, “Flexible Heteroarotinoids (FlexHets) Exhibit Improved Therapeutic Ratios as Anti-Cancer Agents over Retinoic Acid Receptor Antagonists,” Investigational New Drugs, Vol. 23, No. 5, 2005, pp. 417-428. doi:10.1007/s10637-005-2901-5
[52] T. C. Le, K. D. Berlin, S. D. Benson, M. A. Eastman, G. Bell-Eunice, A. C. Nelson and D. M. Benbrook, “Heteroarotinoids with Anti-Cancer Activity against Ovarian Cancer Cells,” Open Medicinal Chemistry Journal, Vol. 1, 2007, pp. 11-23. doi:10.2174/1874104500701010011
[53] T.-Z. Liu, B. Hannafon, L. Gill, B. Kelly and D. M. Benbrook, “Flex-Hets Differentially Induce Apoptosis in Cancer over Normal Cells by Directly Targeting Mitochondria,” Molecular Cancer Therapy, Vol. 6, 2007, pp. 1814-1822. doi:10.1158/1535-7163.MCT-06-0279
[54] P. Masamha and D. Benbrook, “Cyclin D1 Degradation Is Sufficient to Induce G1 Cell Cycle Arrest despite Constitutive Expression of Cyclin E2 in SHetA2-Treated Ovarian Cancer Cells,” Cancer Research, Vol. 69, 2009, pp. 6565-6572. doi:10.1158/0008-5472.CAN-09-0913
[55] T. Liu, C. P. Masamha, S. Chengedza, K. D. Berlin, S. Lightfoot, F. He and D. M. Benbrook, “Development of Flexible-Heteroarotinoids for Kidney Cancer,” Molecular Cancer Therapeutics, Vol. 8, No. 5, 2009, pp. 1227-1238. doi:10.1158/1535-7163.MCT-08-1069
[56] K. C. Moxley, S. Chengedza and D. Mangiaracina, “Induction of Death Receptor Ligand-Mediated Apoptosis in Epithelial Ovarian Carcinoma: The Search for Sensitizing Agents,” Gynecologic Oncology, Vol. 115, No. 3, 2009, pp. 438-442. doi:10.1016/j.ygyno.2009.09.007
[57] F. A. Mic, A. Molotkov, D. M. Benbrook and G. Duester, “Retinoid Activation of RAR but Not RXR Is Sufficient for Mouse Embryonic Development,” Proceedings of the National Academy of Science, Vol. 100, No. 12, 2003, pp. 7135-7140. doi:10.1073/pnas.1231422100
[58] K.-H. Chun, D. M. Benbrook, K. D. Berlin, W. K. Hong and R. Lotan, “Induction of Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines by Heteroarotinoids through a Mitochondrial Dependent Pathway,” Cancer Resesearch, Vol. 63, 2003, pp. 3826-3832. http://cancerres.aacr journals.org/content/63/ 13/3826.long
[59] E. Garattini, M. Gianni and M. Terao, “Retinoid Related Molecules an Emerging Class of Apoptotic Agents with Promising Therapeutic Potential in Oncology: Pharmacological Activity and Mechanisms of Action,” Current Pharmaceutical Design, Vol. 10, No. 4, pp. 433-448, 2004. doi:10.2174/1381612043453351
[60] N. Colombo, F. Formelli, M. G. Cantu, G. Parma, M. Gasco, A. Argusti, A. Santinelli, R. Montironi, E. Cavadini, L. Baglietto, A. Guerrieri-Gonzaga, G. Viale and A. Decensi, “A Phase I-II Preoperative Biomarker Trial of Fenretinide in Ascitic Ovarian Cancer,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 15, No. 10, 2006, pp. 1914-1919. doi:10.1158/1055-9965.EPI-06-0183
[61] M. Cazzaniga, C. Varricchio, C. Montefrancesco, I. Feroce and A. Guerrieri-Gonzaga, “Fenretinide (4-HPR): A Preventive Chance for Women at Genetic and Familial Risk?” Journal of Biomedicine & Biotechnology, Vol. 2012, No. 2012, 2012, Article ID: 172897. doi:10.1155/2012/172897
[62] Y. Zhang, Y. Hua, D. M. Benbrook, J. M. Covey, G. Dai, Z. Liu and K. K. Chan, “High Performance Liquid Chromatographic Analysis and Preclinical Pharma-cokinetics of the Heteroarotinoid Antitumor Agent, SHetA2,” Cancer Chemotherapy & Pharmacology, Vol. 58, No. 5, 2006, pp. 561-569. doi:10.1007/s00280-006-0211-z
[63] R. S. Doppalapudi, E. S. Riccio, Z. Davis, S. Menda, A. Wang, N. Du, C. Green, L. Kopelovich, C. V. Rao, D. M. Benbrook and I. M. Kapetanovic, “Genotoxicity of the Cancer Chemopreventive Drug Candidates CP-31398, SHetA2, and Phospho-Ibuprofen,” Mutation Research, Vol. 746, No. 1, 2012, pp. 78-88. doi:10.1016/j.mrgentox.2012.03.009
[64] K. K. Kabirov, I. M. Kapetanovic, D. M. Benbrook, N. Dinger, I. Mankovskaya, A. Zakharov, C. Detrisac, M. Pereira, T. Martín-Jiménez, E. Onua, A. Banerjee, R. B. van Breemen, D. Nikolic, L. Chen and A. V. Lyubimov, “Oral Toxicity and Pharmacokinetic Studies of SHetA2, a New Chemopreventive Agent, in Rats and Dogs,” Drug and Chemical Toxicology, Vol. 36, No. 3, 2012, pp. 284-295. doi:10.3109/01480545.2012.710632
[65] Z. Liu, Y. Zhang, Y. F. Hua, J. M. Covey, D. M. Benbrook and K. K. Chan, “Metabolism of a Sulfur-Containing Heteroarotionoid Antitumor Agent, SHetA2, Using Liquid Chromatography/Tandem Mass Spectrometry,” Rapid Communications in Mass Spectrometry, Vol. 22, No. 21, 2008, pp. 3371-3381. doi:10.1002/rcm.3744
[66] J. J. Emeiss and C. J. Edgell, “Fibrinolytic Properties of a Human Endothelial Hybrid Cell Line (Ea.hy 926),” Blood, Vol. 71, 1988, pp. 1669-1675. http://bloodjournal.hema tologylibrary.org/content/71/ 6/1669.long
[67] D. S. Grant, P. I. Lelkes, K. Fukuda and H. K. Kleinman, “Intracellular Mechanisms Involved in Basement Membrane Induced Blood Vessel Differentiation in Vitro,” In Vitro Cellular and Developmental Bioliology, Vol. 27, No. 4, 1991, pp. 327-336. doi:10.1007/BF02630910
[68] C. J. Kuo, K. R. J. LaMontagne, G. Garcia-Cardena, B. D. Ackley, D. Kalman, S. Park, R. Christofferson, J. Kamihara, Y.-H. Ding, K.-M. Lo, S. Gillies, J. Folkman, R. C. Mulligan and K. Javaherian, “Oligomerization-Dependent Regulation of Motility and Morphogenesis by the Collagen XVIII NC1/Endostatin Domain,” The Journal of Cell Biology, Vol. 152, No. 6, 2001, pp. 1233-1246. doi:10.1083/jcb.152.6.1233
[69] M. Y. Ahn, S. M. Kwon, H. H. Cheong, J. H. Park, J. Lee, S. K. Min, S. G. Ahn and J. H. Yoon, “Toll-Like Receptor 7 Agonist, Imiquimod, Inhibits Oral Squamous Carcinoma Cells through Apoptosis and Necrosis,” Journal of Oral Pathology & Medicine, Vol. 41, No. 7, 2012, pp. 540-546. doi:10.1111/j.1600-0714.2012.01158.x
[70] D. M. Benbrook and A. Long, “Integration of Autophagy, Proteasomal Degradation, Unfolded Protein Response and Apoptosis,” Experimental Oncology, Vol. 34, No. 3, 2012, pp. 286-297. http://exp-oncology.com.ua/article/3596
[71] J. Folkman, “Angiogenesis in Cancer, Vascular, Rheumatoid and Other Disease,” Nature Medicine, Vol. 1, No. 1, 1995, pp. 27-31.
[72] A. Albini, F. Tosetti, V. W. Li, D. M. Noonan and W. W. Li, “Cancer Prevention by Targeting Angiogenesis,” Nature Reviews Clinical Oncology, Vol. 9, No. 9, 2012, pp. 498-509.
[73] T. Myers, S. Chengedza, S. Lightfoot, Y. Pan, D. Dedmond, L. Cole, Y. Tang and D. M. Benbrook, “Flexible Heteroarotinoid (Flex-Het) SHetA2 Inhibits Angiogenesis in Vitro and in Vivo,” Investigational New Drugs, Vol. 27, 2008, pp. 304-318. doi:10.1007/s10637-008-9175-7
[74] S. Bhoola and W. J. Hoskins, “Diagnosis and Management of Epithelial Ovarian Cancer,” Obstetrics & Gynecology, Vol. 107, No. 6, 2006, pp. 1399-1410. doi:10.1097/01.AOG.0000220516.34053.48
[75] J. T. Hartmann and H.-P. Lipp, “Toxicity of Platinum Compounds,” Expert Opinion on Pharmacotherapy, Vol. 4, No. 6, 2003, pp. 889-901. doi:10.1517/14656566.4.6.889

  
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