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.
Highlights
Immune response modifiers (IRMs) are immunotherapy agents that mimic, augment, or require participation of host immune cells for optimal effectiveness [1]
Because melanoma does not respond to cytotoxic chemotherapies, a number of different adjuvant therapies are being investigated including IRMs, interferon (IFN) α2B is the only agent currently approved by the United States (US) Food and Drug Administration (FDA) for melanoma [5]
Cytotoxicity assays demonstrated that imiquimod treatment caused dose-responsive inhibition of cisplatin resistant (OVCAR-3) and cisplatin-sensitive (A2780) ovarian cancer cell lines and the B16 melanoma cell line (Figure 1)
Summary
Immune response modifiers (IRMs) are immunotherapy agents that mimic, augment, or require participation of host immune cells for optimal effectiveness [1]. Efficacy of IRMs for cancer therapy requires that the tumor is capable of eliciting an immune response. Because melanoma does not respond to cytotoxic chemotherapies, a number of different adjuvant therapies are being investigated including IRMs, interferon (IFN) α2B is the only agent currently approved by the United States (US) Food and Drug Administration (FDA) for melanoma [5]. The most promising class of agents being evaluated in melanoma clinical trials consists of drugs that inhibit the BRAF kinase [6]. New drugs with singleagent activity in recurrent ovarian cancer have been developed, an international cooperative trial revealed that response rates or survival were not improved by combination of these drugs with cytotoxic chemotherapies [10]
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