Antitumor drug cross-resistance in vivo in a murine P388 leukemia resistant to ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - ylcarbamate 2-hydroxyethanesulfonate hydrate (NSC 370,147) 370147.

Ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7- ylcarbamate 2-hydroxyethane-sulfonate hydrate (NSC 370147) is a potent mitotic inhibitor, which has provided the basis for a candidate for clinical trial. As observed with clinically useful drugs, the development of clinical resistance to NSC 370147 will probably be encountered. Information concerning resistance to NSC 370147 should aid in the design of strategies for the optimal clinical use of the drug. A P388 leukemia resistant to NSC 370147 (P388/NSC 370147) was isolated and its in vivo cross-resistance profile was determined. The P388/NSC 370147 line was cross-resistant to vincristine but was not cross-resistant to doxorubicin, etoposide, cisplatin, melphalan, methotrexate, or 5-fluorouracil. This information plus other in vivo cross-resistance data [Waud et al. (1990) Cancer Res 50: 3239] suggests that NSC 370147 may be useful in non-cross-resistant combinations with doxorubicin, melphalan, cisplatin, or methotrexate. The lack of cross-resistance of P388/NSC 370147 to doxorubicin and etoposide shows that resistance to NSC 370147 does not involve multidrug resistance and suggests that the mdr1 gene is not involved in resistance to NSC 370147.