In vitro pharmacology of cryptophycin 52 (LY355703) in human tumor cell lines

Propose: Cryptophycin 52 (LY355703) is a new member of the cryptophycin fam ily of antitumor agents that is currently undergoing clinical evaluation fo r cancer chemotherapy. The mechanism of action of the cryptophycin class of compounds is associated with an action on microtubules. This report detail s the pharmacological profile of this new clinical compound in a panel of h uman tumor cell lines. Methods: Antiproliferative effects of cryptophycin 5 2 were measured indirectly by detection of the metabolic reduction of alama rBlue(R) Cytoxicity was assessed by enzymatic dye activation (calcein AM) c ombined with dye exclusion (ethidium homodimer) and by clonogenicity assay. Cell cycle effects were evaluated using flow cytometry and fluorescence mi croscopy. Results: Both antiproliferative and cytotoxic effects of cryptoph ycin 52 were concentration- and time-dependent. IC50 values for antiprolife rative activity in both solid and hematologic tumor cell lines were in the low picomolar range, and without exception, were significantly below values for the antimitotic agents paclitaxel and vinblastine. Flow cytometry and microscopic examination of tumor cells treated with cryptophycin 52 indicat ed that they accumulated in the mitotic phase of the cell cycle. Cryptophyc in 52 was tested for its sensitivity to multidrug-resistance in several pai red cell lines in which a sensitive parental line was matched with a multid rug-resistant derivative line. The resistant lines have been shown to over express Pgp and/or MRP multidrug-resistance transport factors. Compared to other antimitotic agents (paclitaxel, vinblastine, vincristine), the potenc y of cryptophycin 52 was shown to be minimally affected in multidrug-resist ant cells compared to their sensitive parental lines. Conclusion: Cryptophy cin 52 has potent antimitotic, antiproliferative and cytotoxic activity in in vitro human tumor cell models. Tt is significantly more potent and less sensitive to multidrug resistance mechanisms than other antimitotic antitum or agents currently used in cancer therapy. These characteristics may trans late into therapeutic advantages for the clinical use of cryptophycin 52 in cancer chemotherapy.