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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

has been cited by the following article:

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

  AUTHORS: Mark F. Naylor, David M. Thompson, Stan Lightfoot, Doris Mangiaracina Benbrook

  KEYWORDS: Melanoma; Ovarian Cancer; Heteroarotinoids; Flex-Hets; SHetA2; Apoptosis

  JOURNAL NAME: Journal of Cancer Therapy, Vol.4 No.6A, July 4, 2013

  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.