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-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.
Houghton
P J
PJ
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38101.
Cheshire
P J
PJ
Hallman
J C
JC
Gross
J L
JL
McRipley
R J
RJ
Sun
J H
JH
Behrens
C H
CH
Dexter
D L
DL
Houghton
J A
JA
D000230:Adenocarcinoma / Q000188:drug therapy; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002648:Child; D003110:Colonic Neoplasms / Q000188:drug therapy; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000627:therapeutic use*; D008698:Mesylates / Q000627:therapeutic use*; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D012208:Rhabdomyosarcoma / Q000188:drug therapy; D059004:Topoisomerase I Inhibitors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007546:Isoquinolines; D008698:Mesylates; D059004:Topoisomerase I Inhibitors; C084899:bisnafide