Cryptophycins: A novel class of potent antimitotic antitumor depsipeptides

The antitumor cryptophycins are synthetic derivatives of the desipeptide cr yptophycins isolated from the cyanobacterium Nostoc sp. Cryptophycin 52 tha t is currently in clinical trial in solid tumors, is prepared by total synt hesis Of four key fragments that are Coupled to form the final product. The mechanism of anticancer activity of the cryptophycins has been associated with their destabilization of microtubules and-with their induction of bcl- 2 phosphorylation leading to apoptosis. The cryptophycins maintain activity against ovarian and breast carcinoma cells that overexpress the multidrug resistance efflux pump P-glycoprotein. Cryptophycin 52 has demonstrated a b road range of antitumor activity against both murine and human tumors. In t he human MX-I breast carcinoma xenograft cryptophycin 55 produced greater-t han- additive tumor response in combination with 5-fluorouracil. In human n on-small cell lung carcinoma and human small cell carcinoma xenografts, adm inistration of the cryptophycins along with gemcitabine, cisplatin or carbo platin resulted in antitumor activity greater than either agent alone. The cryptophycins appear to be additive with fractionated radiation therapy in the human H460 non-small cell lung carcinoma. In the human HCT116 colon car cinoma, the cryptophycins resulted in a greater than additive tumor respons e when administered sequentially with 5-fluorouracil or irinotecan. Treatme nt of animals bearing intraperitoneal human OVCAR-2 ovarian carcinoma with cryptophycin 52 resulted in survival times that were greater than those ach ieved with docetaxel or paclitaxel. Cryptophycin 52 is currently in early c linical testing.