Cryptophycin 52 and cryptophycin 55 in sequential and simultaneous combination treatment regimens in human tumor xenografts.

Abstract

The antitumor activity of cryptophycin 52 (C52) and cryptophycin 55 (C55) in sequential and simultaneous combination treatment regimens in human tumor xenografts models was explored. The antitumor activity of C52 and C55 was compared alone and in sequential combination with gemcitabine or paclitaxel in four lung cancer models, H460 and Calu-6 NSCLC and SW2 and H82 small cell lung carcinoma. The combination of C52 followed by gemcitabine was additive in three tumors and greater-than-additive in the fourth. The combination of C55 followed by gemcitabine was additive in three tumors and less-than-additive in the fourth. The combination of C52 followed by paclitaxel was greater-than-additive in one tumor, additive in one tumor and less-than-additive in two tumors. The combination of C55 followed by paclitaxel was greater-than-additive in two tumors and less-than-additive in two tumors. The simultaneous combination of C52 or C55 with fractionated radiation therapy was assessed in the H460 NSCLC tumor. Both cryptophycins produced a tumor response that was additive along with radiation therapy. The HCT116 colon carcinoma was used to compare the antitumor activity of simultaneous or sequential combination of 5-fluorouracil or irinotecan with C52. C52 produced greater-than-additive tumor response when administered either simultaneously with or sequentially with 5-fluorouracil or iriniotecan. Finally, when administered to animals bearing intraperitoneal OVCAR-3 ovarian carcinoma, C52, docetaxel and paclitaxel resulted in mean survival times of 123, 80 and 85 days compared with 72 days in the untreated controls. In combination with carboplatin, C52, docetaxel and paclitaxel resulted in mean survival times of 140, 105 and 135 days. Cryptophycins have the potential to be useful chemotherapeutic agents in a wide variety of clinical combinations regimens.