Potentiation of docetaxel antitumor activity by batimastat against mouse forestomach carcinoma
Abstract:
Docetaxel is a chemical compound belonging to the taxoid class of anticancer agents. Batimastat (BB-94) is the first matrix metalloproteinase inhibitor entering clinical trials. To improve the treatment of tumors, we studied the combined effects of docetaxel and batimastat on mouse forestomach carcinoma (MFC), and compared them with doxorubicin. In vitro growth curve analysis, MTT assay, and clonogenic assay were used to determine the cytotoxic effect of docetaxel or/and BB-94 on MFC. They showed that docetaxel, but not BB-94, had a significant cytotoxicity and that the effect of docetaxel was not enhanced by BB-94. In an early stage MFC tumor model, an obvious antitumor effect of docetaxel or doxorubicin given iv at maximum tolerated dose (MTD) was observed. Tumor growth inhibition was greater for docetaxel + BB-94 (96.0%) than for doxorubicin + BB-94 (88.0%), docetaxel (89.0%), doxorubicin (68.0%), and BB-94 (33.0%). Docetaxel showed activity against advanced stage MFC tumor in a dose-dependent manner and was more effective at MTD than doxorubicin, with 4/5 regression, 46.5 days tumor growth delay, and 2.8 log10 tumor-cell kill. Our results suggest that docetaxel is an effective new cytotoxic drug against MFC tumor and that BB-94 enhances the antitumor activity of docetaxel in the dose and schedule used.
Insights
Docetaxel demonstrates significant anticancer activity against mouse forestomach carcinoma (MFC). Combining docetaxel with Batimastat (BB-94) enhances its antitumor effects, suggesting a promising therapeutic strategy.
Area of Science:
- Oncology
- Pharmacology
Background:
- Docetaxel is a taxoid anticancer agent.
- Batimastat (BB-94) is a matrix metalloproteinase inhibitor.
- Combined therapies are explored to improve tumor treatment.
Purpose of the Study:
- To evaluate the combined effects of docetaxel and Batimastat (BB-94) on mouse forestomach carcinoma (MFC).
- To compare these combined effects with doxorubicin treatment.
- To determine the efficacy of docetaxel and BB-94 as monotherapies and in combination.
Main Methods:
- In vitro: growth curve analysis, MTT assay, clonogenic assay.
- In vivo: early and advanced stage MFC tumor models.
- Assessment of docetaxel, BB-94, doxorubicin, and their combinations at maximum tolerated dose (MTD).
Main Results:
- Docetaxel exhibited significant cytotoxicity in vitro; BB-94 did not enhance this effect.
- In vivo, docetaxel + BB-94 showed superior tumor growth inhibition (96.0%) compared to doxorubicin + BB-94 (88.0%) and monotherapies.
- Docetaxel demonstrated dose-dependent activity against advanced MFC, outperforming doxorubicin in regression, tumor growth delay, and cell kill.
Conclusions:
- Docetaxel is an effective cytotoxic agent against mouse forestomach carcinoma.
- Batimastat (BB-94) enhances the antitumor activity of docetaxel when used in combination at the specified dose and schedule.
- The combination of docetaxel and BB-94 presents a potential therapeutic strategy for MFC treatment.
