Relationships between tumor responsiveness, vincristine pharmacokinetics and arrest of mitosis in human tumor xenografts

Abstract

Tumor responsiveness to vincristine (VCR) was determined in xenografts of human rhabdomyosarcoma (RMS), in sublines of RMS selected in vivo for VCR resistance, in a KB line (KB-ChR8-5) selected in vitro for colchicine resistance, and in a colon adenocarcinoma (GC3). Sensitivity to VCR was associated with prolonged retention of VCR by the tumors after a single i.p. injection, whereas in tumors with acquired or intrinsic VCR resistance the drug was eliminated more rapidly. The sensitive tumors with prolonged retention of drug also showed increased levels of mitotic accumulation for up to 72 hr following VCR administration. There were good correlations between VCR sensitivity, VCR retention and the proposed mechanism of VCR cytotoxicity-mitotic arrest. A model has been developed consistent with data obtained that can explain the responsiveness to VCR of a series of human tumor xenografts irrespective of their tissue of origin.