Abstract 2922: NDC-1308 inhibits growth of lung and pancreatic tumors in vivo by blocking chromosome replication of cancer cells

Abstract

Abstract Identification of the cellular mechanisms that alter normal cell growth may be exploited for creating new drugs that treat cancers with unmet needs. For example, recent evidence by our group, and others, suggests that proliferation of lung and pancreatic cancer cells may be controlled by the estrogen receptors alpha (ER-alpha) and beta (ER-beta). If accurate, designing drugs that enhance the proposed inhibitory function of ER-beta versus the stimulatory function of ER-alpha, should lead to cessation of cell division and potentially to cell death. We previously demonstrated that an estradiol-like compound, NDC-1308, is cytotoxic to 14 different tumor cell lines in vitro with an EC50 of 10-20 uM. As predicted, receptor binding studies confirmed that NDC-1308 binds preferentially to ER-beta compared to ER-alpha. A more detailed in vitro analysis showed that NDC-1308 causes a substantial reduction in the transcription of 27 genes involved in chromosomal replication, likely disrupting the cell cycle of the cancer cells. To determine the efficacy of NDC-1308 to kill tumor cells in vivo, xenograft studies were carried out using SCID mice injected with A549 (lung) and BxPC3 (pancreas) tumor cell lines. Mice (N=15 per treatment group) were administered either 8, 16 or 24 mg/kg of NDC-1308 via tail vein injection. Depending on the schedule, the mice were dosed every other day or every third day and the tumor weights followed for two additional weeks after ending treatment. The results show that tumor size was substantially smaller (2 to 3-fold) in NDC-1308 treated animals versus untreated controls. We conclude that intravenous administration of NDC-1308 can cause a cessation of tumor growth in a mouse model of lung and pancreatic cancer. Consistent with the proposed mechanism of action and recent rat pharmacokinetic data (t1/2=120min), increasing the dose or decreasing the time between doses enhanced the effect of NDC-1308 on tumor growth in the xenograft model. Future studies will include large animal safety and toxicity studies leading to IND submission and Phase I clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2922.