Synergistic interaction between cyclophosphamide or paclitaxel and the bioreductive compound NLCPQ-1, in vivo.

Abstract

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.

• Authors: M V Papadopoulou, M Ji, W D Bloomer
• Journal: Oncology research (Oncol Res) Vol. 13 Issue 12 Pg. 561-6 ( 2003) ISSN: 0965-0407 [Print] United States
• PMID: 12899246 (Publication Type: Journal Article)

Chemical References

• 9-(3-(2-nitro-1-imidazolyl)-propylamino)cycopenteno(b)quinoline
• Antineoplastic Agents, Alkylating
• Antineoplastic Agents, Phytogenic
• Nitroimidazoles
• Quinolines
• Cyclophosphamide
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Cyclophosphamide (administration & dosage, pharmacology)
• Drug Administration Schedule
• Drug Synergism
• Female
• Mammary Neoplasms, Experimental (drug therapy)
• Mice
• Mice, Inbred BALB C
• Nitroimidazoles (administration & dosage, pharmacology)
• Paclitaxel (administration & dosage, pharmacology)
• Quinolines (administration & dosage, pharmacology)
• Tumor Cells, Cultured