Antifolates can potentiate topoisomerase II inhibitors in vitro and in vivo.
Antifolates have been shown to increase the DNA strand breaks produced by the topoisomerase inhibitor etoposide. PT523 is a potent new antifolate that cannot be polyglutamated. Human SCC-25 squamous carcinoma cells were exposed to methotrexate, trimetrexate or PT523 at a concentration of 5 microM for 24 h along with various concentrations of etoposide or novobiocin during the final 2 h. Isobologram analysis of the treatment combinations indicated that exposure of the cells to PT523/etoposide, methotrexate/etoposide, PT523/novobiocin, methotrexate/novobiocin and trimetrexate/novobiocin resulted in greater than additive cytotoxicity. DNA alkaline elution studies with the same drug combinations indicated that there were three- to four-fold increases in the radiation equivalent (rad equivalent) strand breaks in the cellular DNA with etoposide or novobiocin along with the antifolate compared with the topoisomerase II inhibitors alone. Tumor growth delay studies were carried out in the murine SCC VII squamous carcinoma. PT523 (0.5 mg/kg) and methotrexate (2 mg/kg) were administered by 7-day continuous infusion while trimetrexate (3.75 mg/kg) was administered intraperitoneally daily on days 7-9. Etoposide (10 mg/kg) and novobiocin (100 mg/kg) were administered intraperitoneally on alternate days (7, 9, 11). The combinations of PT523 with etoposide or novobiocin were significantly more effective than methotrexate and etoposide or novobiocin, producing tumor growth delays of 8.4 days and 6.9 days, respectively. Overall, the antifolate/topoisomerase II inhibitor treatment combinations produced tumor growth delays that were apparently additive to greater than additive.
Holden
S A
SA
Dana-Faber Cancer Institute, Boston, MA 02115, USA.
Teicher
B A
BA
Robinson
M F
MF
Northey
D
D
Rosowsky
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005047:Etoposide / Q000627:therapeutic use / Q000633:toxicity; D005493:Folic Acid Antagonists / Q000627:therapeutic use / Q000633:toxicity*; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D008809:Mice, Inbred C3H; D009675:Novobiocin / Q000627:therapeutic use / Q000633:toxicity; D009952:Ornithine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D011622:Pterins / Q000627:therapeutic use* / Q000633:toxicity*; D059005:Topoisomerase II Inhibitors; D016597:Trimetrexate / Q000627:therapeutic use / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D005493:Folic Acid Antagonists; D011622:Pterins; D059005:Topoisomerase II Inhibitors; C085590:N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine; D009675:Novobiocin; D005047:Etoposide; D009952:Ornithine; D016597:Trimetrexate; D008727:Methotrexate