Antitumor activity of cryptophycins: effect of infusion time and combination studies

Introduction/Purpose: Cryptophycins are a family of antitubulin antitumor a gents. A synthetic cryptophycin derivative (LY355703, CRYPTO 52) is in earl y clinical evaluation. The effect of infusion time on the antitumor activit y of four cryptophycins was assessed in rats bearing the 13762 mammary carc inoma and combination treatment regimens were assessed in nude mice bearing human tumor xenografts. Methods: The cryptophycins were prepared in 2% PEG 300/8% cremophor/90% normal saline and delivered by jugular vein catheter o n days 7, 9 and 11 post tumor implant to 13762 tumor-bearing rats. The cryp tophycins prepared in the same formulation were administered by intravenous bolus injection on an alternate day schedule for five doses to human tumor xenograft bearing nude mice. Results: An infusion time of 2 h in the rats increased the tumor growth delay produced by CRYPTO 52 and CRYPTO 55, while increasing the infusion time to 6 h continued to increase the tumor growth delay for CRYPTO 292 and CRYPTO 296. Administering CRYPTO 292 at a higher dose two times was more effective than administering it at a lower dose thr ee times. The tumor growth delays produced by the cryptophycins in the rat 13762 mammary carcinoma were greater than those with cisplatin, doxorubicin , 5-fluorouracil and 5 x 3 Gray and comparable with cyclophosphamide and ge mcitabine. Combination studies were carried out in human tumor xenografts i ncluding the MX-1 breast carcinoma, the Calu-6 non-small cell lung carcinom a, the H82 small cell lung carcinoma and the SW-2 small cell lung carcinoma . CRYPTO 52 and CRYPTO 55 combined with doxorubicin, paclitaxel and 5-fluor ouracil to form highly effective regimens against the human MX-I breast car cinoma. CRYPTO 52 and CRYPTO 55 were also highly effective against the thre e lung carcinoma xenografts when combined with the antitumor platinum compl exes, cisplatin, carboplatin or oxaliplatin. Conclusions: Cryptophycins rep resent a promising new class of antitumor agents that may be optimally admi nistered by intravenous infusion and in combination with doxorubicin, pacli taxel and 5-fluorouracil.