Synergistic interaction between cyclophosphamide or paclitaxel and the bioreductive compound NLCPQ-1, in vivo.
The antitumor effect of cyclophosphamide (CPM) and paclitaxel was investigated in BALB/c mice bearing EMT6 tumors, in combination with the bioreductive compound NLCPQ-1 by using the in vivo/in vitro assay as the endpoint. An optimum administration schedule for a synergistic interaction between NLCPQ-1 and CPM/paclitaxel was determined and dose modification factors (DMF) were calculated for antitumor effect and bone marrow toxicity. All drugs were given by IP injection; NLCPQ-1 at 15 mg/kg, which is much less than its maximally tolerated dose (MTD greater than 50 mg/kg), paclitaxel up to 25 mg/kg, and CPM up to 200 mg/kg. Bone marrow toxicity studies were performed in parallel by using a modified CFU-GM assay. A schedule-dependent synergistic interaction was observed for both chemotherapeutic agents combined with NLCPQ-1 but with entirely different patterns, as has been previously seen with the analog NLCQ-1. The optimal degree of potentiation, P (percentage of tumor cells that were killed due to clear potentiation), was 31 and 33 when NLCPQ-1 was administered 2 h before CPM and 3-3.5 h after paclitaxel, respectively. At the above time schedules, NLCPQ-1 modified the dose of CPM and paclitaxel, for 60% tumor cell killing, by a factor of 1.8 and 2.1, respectively. Bone marrow toxicity was not enhanced by combining either chemotherapeutic agent with NLCPQ-1. Comparison with results from previous similar studies with NLCQ-1 revealed that, on a molar basis, NLCPQ-1 was a less potent chemosensitizer than NLCQ-1. However, the results still suggest a potential clinical use of NLCPQ-1 as an adjuvant to CPM or paclitaxel therapy against solid tumors.
Papadopoulou
M V
MV
The Department of Radiation Medicine at Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA. m-papadopoulou@nwu.edu
Ji
M
M
Bloomer
W D
WD
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C106788:9-(3-(2-nitro-1-imidazolyl)-propylamino)cycopenteno(b)quinoline; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D009593:Nitroimidazoles; D011804:Quinolines; D003520:Cyclophosphamide; D017239:Paclitaxel