Therapeutic efficacy of the cyclopropylpyrroloindole, carzelesin, against xenografts derived from adult and childhood solid tumors.
The therapeutic efficacy of the sequence-selective, DNA minor-groove-binding alkylating agent carzelesin was evaluated against a series of human tumor xenografts growing at the s.c. site. The model consisted of seven colon adenocarcinomas, and six pediatric rhabdomyosarcomas. In addition, carzelesin was evaluated against xenografts selected in situ for resistance to vincristine, melphalan, and topotecan. Carzelesin was given as a single i.v. injection, and tumor volumes were determined at 7-day intervals. At the highest dose [0.5 mg/kg, the dose producing 10% lethality (LD10)]), carzelesin significantly inhibited growth in four of six colon tumor lines, causing a high proportion of partial regressions in one of seven lines and complete regressions of VRC5 colon tumors. At 0.25 mg/kg, significant growth inhibition was determined in only two of seven colon tumor lines with infrequent volume regressions. Carzelesin given at the highest nonlethal dose level significantly inhibited the growth of each of six rhabdomyosarcomas, causing a high frequency of partial or complete regressions in four of six tumor lines. There was no apparent cross-resistance to carzelesin in two rhabdomyosarcomas selected for vincristine resistance (Rh12/VCR, Rh18/VCR) or in Rh28/LPAM xenografts selected for primary resistance to the bifunctional alkylating agent melphalan. Interestingly, carzelesin maintained full activity against Rh18/TOPO tumors selected in situ for resistance to topotecan, whereas the colon tumor VRC5/TOPO, selected in a similar manner, was completely resistant to this agent.
Houghton
P J
PJ
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38101, USA.
Cheshire
P J
PJ
Hallman
J D
JD
Houghton
J A
JA
D000230:Adenocarcinoma / Q000188:drug therapy*; D000293:Adolescent; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001572:Benzofurans / Q000627:therapeutic use*; D002648:Child; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D012208:Rhabdomyosarcoma / Q000188:drug therapy*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D001572:Benzofurans; D000080890:Duocarmycins; D007211:Indoles; C076570:carzelesin