Schedule-dependent potentiation of chemotherapeutic drugs by the bioreductive compounds NLCQ-1 and tirapazamine against EMT6 tumors in mice.
OBJECTIVE
Comparisons of schedule-dependent interactions between the hypoxic cytotoxins NLCQ-1/ tirapazamine (TPZ) and various chemotherapeutic drugs in BALB/c mice bearing EMT6 tumors.


METHODS
The antitumor effects of the single or combined drugs were assessed with various administration time intervals using the in vivo-in vitro clonogenic assay as the endpoint. The chemotherapeutic drugs tested were cisplatin (cisDDP), melphalan (L-PAM), cyclophosphamide (CPM), 5-fluorouracil (5-FU), doxorubicin (Doxo), etoposide (VP-16) and Taxol at doses of 8, 5, 100, 150, 12, 35 and 20 mg/kg, respectively. NLCQ-1 was given at 10 mg/kg (28% of its single LD50 value) and TPZ was given at 30 mg/kg (38% of its single LD50 value). All drugs were given by i.p. injection in saline or as commercially available pharmaceutical solutions.


RESULTS
Schedule-dependent synergistic interactions with different patterns for each bioreductive drug were observed with almost all of the chemotherapeutic agents examined. Potentiation accounting for more than 25% of the total tumor cell killing was observed with NLCQ-1/TPZ and cisDDP, L-PAM, CPM, 5-FU and Taxol at the optimal administration intervals. Potentiation accounting for 70% of the total tumor cell killing was found with NLCQ-1 and CPM.


CONCLUSIONS
These results suggest a potential clinical use of NLCQ-1/TPZ as adjuvants to certain chemotherapeutic agents.
Papadopoulou
M V
MV
The Radiation Medicine Institute, Evanston Northwestern Healthcare, IL 60201, USA. m-papadopoulou@nwu.edu
Ji
M
M
Bloomer
W D
WD
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D008558:Melphalan / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C434187:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride; D007093:Imidazoles; D011804:Quinolines; D014227:Triazines; D000077704:Tirapazamine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D002945:Cisplatin; D008558:Melphalan; D005472:Fluorouracil