Cross-resistance of drug-resistant murine leukemias to deoxyspergualin (NSC 356894) in vivo

Summary

Deoxyspergualin, the 15-deoxy derivative of the antibiotic spergualin, is a novel guanidino analog structurally related to spermine. Deoxyspergualin has significant activity in selected experimental tumor models, and clinical trials have been initiated. Described here are in vivo evaluations of the therapeutic activity of deoxyspergualin against murine leukemia lines specifically resistant to eight clinically useful antitumor drugs. These were P388 lines resistant to doxorubicin, vincristine, L-phenylalanine mustard, cisplatin, ara-C, and methotrexate and L1210 lines resistant to 5-FU, L-phenylalanine mustard, and cyclophosphamide. Sensitivity to deoxyspergualin was evaluated in parallel comparisons of each resistant leukemia to the sensitive line from which it had been derived. All experiments were repeated at least once for confirmation of results. Responses were quantitated in terms of the change in tumor cell numbers from the beginning of treatment to the end of treatment as estimated from the median survival times of dying mice. The results indicated that P388 leukemia resistant to cisplatin (P388/DDPt) was cross-resistant to deoxyspergualin. No cross-resistance was observed in leukemias resistant to doxorubicin, vincristine, ara-C, methotrexate, or cyclophosphamide. L1210 resistant to 5-FU (L1210/5-FU) was collaterally sensitive to deoxyspergualin. Although cross-resistance was also observed in P388/L-PAM, L1210/L-PAM retained sensitivity to deoxyspergualin. Total glutathione concentrations in P388/L-PAM and L1210/L-PAM provided no apparent explanation for this unexpected result. It may be tentatively concluded that resistance to cisplatin, L-PAM, or other DNA alkylators or cross-linkers may increase the potential for cross-resistance to deoxyspergualin. This conclusion requires verification with additional alkylating agents, with drug-resistant human tumor cell lines, and with prospective clinical studies. However, it has present implications for the mechanism(s) of deoxyspergualin activity, for the selection of patients for clinical trials of this investigational new drug, and for the design of noncross-resistant drug combinations.