Abstract 978: Synergistic activity of EP-100 and chemotherapies in cancer cell lines.

Abstract

Abstract EP-100, a targeted anti-cancer drug comprised of a lytic peptide fused to Luteinizing Hormone Releasing Hormone (LHRH), is in Phase 2 clinical trial in tumors that over-express LHRH receptors in combination with paclitaxel. It kills cancer cells by membrane disruption. EP-100 was tested in combination with paclitaxel, vinorelbine, doxorubicin, cisplatinum, vincristine and 5 fluorouracil (5FU) in vitro. The sequence of adding EP-100 to the chemotherapeutics was tested in consideration of their half-lives (hours) than EP-100 (minutes). EP-100 was added to the cells before or after treatment with the chemotherapeutics to determine the order of treatment for maximum synergy. Cells were cultured in the presence of each single agent and in combination with EP-100 for 72h. Data were analyzed as IC50 values for each single drug and the combination with EP-100. Combination indices (CI) on interaction of EP-100 and each chemotherapeutic were determined. EP-100 alone was cytotoxic at low uM concentrations in LHRH receptor (+), multi-drug resistant human uterine sarcoma cell line MES-SA-Dx5 and a human breast cancer cell line MDA-MB-231 after 72 h incubation. Both cell lines were resistant to paclitaxel, vinorelbine, vincristine, 5-FU and cisplatinum. MES-SA-Dx5 cells were resistant to doxorubicin. Addition of EP-100 to each of the chemotherapeutics increased sensitivity to all of the drugs except 5-FU (Table 1). Combinations of EP-100 with paclitaxel, vincristine, vinorelbine, doxorubicin and cisplatinum resulted in potentiation of activity in a synergistic manner for both uterine sarcoma and breast cancer cell lines. The combination effects were synergistic with CIs of 0.2. The sequence of exposure was most potent when EP-100 was given first followed by incubation with paclitaxel, doxorubicin or vinorelbine. Table 1 In vitro activities (IC50 - nM) MES-SA-Dx5 Combination Index Potentiation MDA-MB-231 Combination Index Potentiation EP-100 Alone 3044 ± 558 1400 ± 300 Paclitaxel 33.7 ± 2.2 86.2 ± 5.9 EP100+Paclitaxel 0.014 ± 0.002 0.001 6000 15.9 ± 0.8 0.22 5.7 Vincristine 124.7 ± 16.3 26.3 ± 4.1 EP-100+Vincristine 5.7 ± 0.9 0.02 21.7 1.8 ± 0.1 0.09 15 Doxorubicin 32.6 ± 4.3 1.26 ± 0.4 EP-100+Doxorubicin 3.3 ± 0.6 0.09 9.6 1.1 ± 0.04 NA 1 Vinorelbine 63.22 ± 15.9 23.7 ± 3.4 EP-100+Vinorelbine 6.0 ± 1.6 0.06 10.5 3.1 ± 0.9 0.1 7.6 CDDP 54.5 ± 5.8 19.9 ± 6.2 EP-100 + CDDP 8.0 ± 2.6 0.2 6.8 8.1 ± 1.9 0.1 2.5 These results indicate that EP-100 synergizes with paclitaxel, doxorubicin, vinorelbine, vincristine and cisplatinum but not 5-FU in drug resistant human uterine sarcoma and breast cancer cells. Citation Format: Carola Leuschner, Shashi Gavini, Hector W. Alila. Synergistic activity of EP-100 and chemotherapies in cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 978. doi:10.1158/1538-7445.AM2013-978