Enhancement of melphalan activity by inhibition of DNA polymerase-alpha and DNA polymerase-beta.
Our previous studies exploring melphalan resistance in the human rhabdomyosarcoma xenograft TE-671 MR revealed elevation of DNA polymerase-alpha and DNA polymerase-beta. The present study evaluated the alteration of melphalan activity in TE-671 (melphalan-sensitive) and TE-671 MR (melphalan-resistant) subcutaneous xenografts in nude mice after DNA polymerase-alpha was inhibited using aphidicolin glycinate (AG) and DNA polymerase-beta was inhibited using dideoxycytidine (DDC). Administration of AG or DDC did not produce toxicity or demonstrate antineoplastic activity when given alone. AG (90 mg/m2) enhanced the activity of melphalan against TE-671, with growth delays increasing by 8.4, 15.8, and 21.2 days over the regimen with melphalan only. AG (180 mg/m2) only modestly increased melphalan activity against TE-671 MR, with the growth delays increasing from 9.6 and 12.1 days using melphalan alone to 12.1 and 14.5 days using melphalan plus AG. AG (180 mg/m2) plus melphalan (the dose lethal to 10% of animals) produced greater weight loss compared with melphalan alone, whereas DDC plus melphalan produced no additional toxicity. DDC modestly enhanced the activity of melphalan plus AG against TE-671 MR. AG plus O6-benzylguanine did not increase the activity of 1,3-bis(2-chloroethyl)-1-nitrosourea against TE-671 or TE-671 MR. AG (90 mg/m2 and 180 mg/m2) inhibited DNA polymerase-alpha to 80% and 72% of control in TE-671 and 64% and 37% in TE-671 MR, and DDC inhibited DNA polymerase-beta to 59% in TE-671 and 48% in TE-671 MR. These results suggest a role for AG-mediated enhancement of melphalan activity, particularly in the treatment of newly diagnosed, melphalan-sensitive tumors.
Moynihan
K
K
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Elion
G B
GB
Ali-Osman
F
F
Marcelli
S
S
Keir
S
S
Bigner
D D
DD
Friedman
H S
HS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D016590:Aphidicolin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors*; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008297:Male; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012208:Rhabdomyosarcoma / Q000473:pathology; D016047:Zalcitabine / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; C064976:O(6)-benzylguanine; D016590:Aphidicolin; D006147:Guanine; D016047:Zalcitabine; C068151:aphidicolin glycinate; D004256:DNA Polymerase I; D004257:DNA Polymerase II; D008558:Melphalan; D002330:Carmustine