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.