Activity of aphidicolin glycinate alone or in combination with cisplatin in a murine ovarian tumor resistant to cisplatin.
Aphidicolin, a reversible inhibitor of DNA polymerase alpha and delta, has recently been reported to reverse the resistance to cisplatin (DDP) of an ovarian cancer cell line. We investigated the pharmacokinetics of aphidicolin in mice and examined its activity either alone or in combination with DDP in the DDP-sensitive M5076 (M5) murine reticular cell sarcoma as well as in a DDP-resistant subline (M5/DDP). The drug was cleared from plasma very rapidly (clearance, 41.6 ml min-1 kg-1), showing a half-life of 15 min. Aphidicolin concentrations in the tumor were approximately 50% of those found in plasma at steady state. Using several dose schedules and continuous infusions we failed to detect significant antitumor activity for aphidicolin glycinate. Potentiation of the activity of DDP by aphidicolin glycinate was moderate in mice bearing M5 tumor as well as in those bearing M5/DDP tumor. These data do not support the possible clinical use of aphidicolin in combination with DDP. However, further studies should be carried out in different tumor models before this possibility is conclusively ruled out.
Damia
G
G
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Tagliabue
G
G
Zucchetti
M
M
Davoli
E
E
Sessa
C
C
Cavalli
F
F
D'Incalci
M
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016590:Aphidicolin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004357:Drug Synergism; D005260:Female; D006207:Half-Life; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D016590:Aphidicolin; C068151:aphidicolin glycinate; D002945:Cisplatin