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Metallothionein-mediated resistance to multiple drugs can be induced by several anticancer drugs in mice
1Department of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Abstract:
We examined the role of metallothionein in the chemosensitivity of transplanted tumors in mice. The antitumor activities of cisplatin, adriamycin, bleomycin, peplomycin, cyclophosphamide, and melphalan were significantly suppressed when the concentration of metallothionein in the tumor was increased to only twice the control level. On the other hand, the antitumor activities of mitomycin C, 5-fluorouracil, and vinblastine were hardly affected by increases in the concentration of metallothionein in the tumors in mice. Moreover, all the antitumor drugs examined increased the concentration of metallothionein in transplanted tumors to a level that was high enough to suppress the antitumor activity of these drugs. These observations suggest that treatment of patients with certain antitumor drugs might result in the resistance of their tumors to multiple drugs.
Insights
Metallothionein (MT) in tumors can suppress chemotherapy effectiveness. Increased MT levels reduce the efficacy of certain anticancer drugs, potentially leading to multidrug resistance in patients.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Metallothionein (MT) is a protein involved in cellular defense mechanisms.
- The role of MT in tumor chemosensitivity remains incompletely understood.
- Understanding MT's impact is crucial for optimizing cancer treatment strategies.
Purpose of the Study:
- To investigate the influence of metallothionein on the chemosensitivity of transplanted tumors in mice.
- To determine which anticancer drugs are affected by elevated MT levels.
- To explore the potential of MT induction by chemotherapy to cause multidrug resistance.
Main Methods:
- Transplanted tumors in mice were utilized as a model system.
- Tumor metallothionein (MT) concentrations were manipulated and measured.
- The antitumor activities of various chemotherapeutic agents were assessed in vivo.
- The effect of chemotherapy on MT levels within tumors was evaluated.
Main Results:
- Elevated MT levels (twice the control) significantly suppressed the antitumor activity of cisplatin, adriamycin, bleomycin, peplomycin, cyclophosphamide, and melphalan.
- Mitomycin C, 5-fluorouracil, and vinblastine showed minimal sensitivity to increased MT concentrations.
- All tested antitumor drugs increased MT concentration in transplanted tumors to levels that inhibited their own efficacy.
Conclusions:
- Metallothionein plays a significant role in mediating resistance to several key chemotherapeutic agents.
- Chemotherapy-induced MT upregulation may contribute to the development of multidrug resistance in tumors.
- Targeting MT or its induction pathways could be a strategy to enhance chemotherapy effectiveness.