EVALUATION OF A NOVEL BIS-NAPHTHALIMIDE ANTICANCER AGENT, DMP-840, AGAINST HUMAN XENOGRAFTS DERIVED FROM ADULT, JUVENILE, AND PEDIATRIC CANCERS

The new bis-naphthalimide antitumor agent (R,R)2,2'-[1,2-ethanediylbis [imino(1-methyl-2.1- diyl)]bis{5-nitro-1H-benz[de]-isoquinoline-1,3-2H ) dione} dimethanesulfonate (DMP 840) was evaluated against parental a nd multidrug-resistant human KB cell lines in vitro and against these lines growing as xenografts in immune-deprived mice. In vitro, KB8-5 c ells were 50-fold resistant to vincristine but only 16-fold resistant to DMP 840 as measured by clonogenic survival. For in vivo evaluation, DMP 840 was given by i. v. injection daily for 9 days or for 5 days/w eek for 2 consecutive weeks [(dx5)2]. In contrast to the cross-resista nce of KB cell lines in vitro, both KB3-1 and KB8-5 tumors were highly and equally sensitive to DMP 840; only KB3-1 xenografts demonstrated sensitivity to vincristine, which was consistent with the in vitro res ults. DMP 840 was also evaluated against a panel of human tumors compr ising colon adenocarcinoma and rhabdomyosarcoma xenografts. Against ei ght lines of colon adenocarcinoma, DMP 840 caused a high frequency of partial and complete regressions in two lines and significant inhibiti on of growth in two lines. DMP 840 caused complete regressions in five of six lines of advanced rhabomyosarcomas, demonstrating a broad rang e of effective dose levels. The pattern of activity against this tumor panel was similar but not identical to that of two inhibitors of topo isomerase I. There was no cross-resistance to DMP 840 in xenografts se lected for resistance to vincristine or in a rhabdomyosarcoma selected for resistance to the topoisomerase I inhibitor topotecan. In contras t, a colon tumor selected for topotecan resistance was completely resi stant to DMP 840. Slight cross-resistance to DMP 840 was demonstrated in a rhabdomyosarcoma xenograft that was selected for primary resistan ce to melphalan and was cross-resistant to topoisomerase I inhibitors. The pattern of activity and cross-resistance in these tumors was comp ared with that shown by two agents that inhibit topoisomerase I: topot ecan and CPT-11