The new bis-
naphthalimide antitumor agent (R,R)2,2'-[1,2-ethanediylbis[imino(1-methyl-2.1-ethanediyl)]-bis(5 -nitro 1H-benz[de]-
isoquinoline-1,3-2H) dione] dimethanesulfonate (
DMP 840) was evaluated against parental and multidrug-resistant human KB cell lines in vitro and against these lines growing as xenografts in immune-deprived mice. In vitro, KB8-5 cells 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/week for 2 consecutive weeks [(dx5)2]. In contrast to the cross-resistance 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 results.
DMP 840 was also evaluated against a panel of human
tumors comprising
colon adenocarcinoma and
rhabdomyosarcoma xenografts. Against eight lines of
colon adenocarcinoma,
DMP 840 caused a high frequency of partial and complete regressions in two lines and significant inhibition of growth in two lines.
DMP 840 caused complete regressions in five of six lines of advanced
rhabdomyosarcomas, demonstrating a broad range of effective dose levels. The pattern of activity against this
tumor panel was similar but not identical to that of two inhibitors of
topoisomerase I. There was no cross-resistance to
DMP 840 in xenografts selected for resistance to
vincristine or in a
rhabdomyosarcoma selected for resistance to the
topoisomerase I inhibitor topotecan. In contrast, a colon
tumor selected for
topotecan resistance was completely resistant to
DMP 840. Slight cross-resistance to
DMP 840 was demonstrated in a
rhabdomyosarcoma xenograft that was selected for primary resistance to
melphalan and was cross-resistant to
topoisomerase I inhibitors. The pattern of activity and cross-resistance in these
tumors was compared with that shown by two agents that inhibit
topoisomerase I:
topotecan and
CPT-11.