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Multidrug resistance: a transport system of antitumor agents and xenobiotics
1Institute of Applied Microbiology, University of Tokyo, Japan.
Abstract:
Resistance of tumors to a variety of chemotherapeutic agents presents a major problem in cancer treatment. Resistance to such agents as doxorubicin, Vinca alkaloids, and actinomycin D can be acquired by tumor cells after treatment with a single drug. The gene responsible for multidrug resistance, termed mdr1, encodes a membrane glycoprotein (P-glycoprotein) that acts as a pump to transport various cytotoxic agents including various xenobiotics out of the cell. The amount of P-glycoprotein expression has been measured in tumor samples and was found to be elevated in intrinsically drug-resistant cancers of the colon, kidney, and adrenal as well as in some tumors that acquired drug resistance after chemotherapy. The protein was also found to be elevated in cells treated with xenobiotics. P-glycoprotein has been shown to bind anticancer drugs and several resistance-reversing agents including calcium channel blockers, and to be an ATPase. We recently reconstituted the purified P-glycoprotein into artificial liposomes. Reconstituted P-glycoprotein showed ATPase activity, ATP-dependent drug-transport activity, and calcium channel blocker-binding activity. This model provides many advantages for studies of the biochemical functions of P-glycoprotein. In addition to these basic interests, the protein is of considerable interest as a target for cancer chemotherapy because it appears to be involved in both acquired multidrug resistance and intrinsic drug resistance in human cancer. The selective killing of tumor cells expressing P-glycoprotein could be very important in future cancer therapy.
Insights
Tumor resistance to chemotherapy is a major challenge. The P-glycoprotein pump, encoded by the mdr1 gene, actively removes drugs from cancer cells, contributing to both intrinsic and acquired drug resistance.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Tumor resistance to chemotherapeutic agents is a significant obstacle in cancer treatment.
- Acquired resistance can develop after exposure to single drugs, leading to multidrug resistance (MDR).
- The mdr1 gene product, P-glycoprotein, is a membrane pump exporting cytotoxic agents and xenobiotics from cells.
Purpose of the Study:
- To investigate the role of P-glycoprotein in multidrug resistance.
- To characterize the biochemical functions of purified P-glycoprotein.
- To explore P-glycoprotein as a potential target for cancer chemotherapy.
Main Methods:
- Measurement of P-glycoprotein expression in tumor samples.
- Reconstitution of purified P-glycoprotein into artificial liposomes.
- Assays for ATPase activity, drug transport, and drug binding in reconstituted systems.
Main Results:
- Elevated P-glycoprotein expression was observed in intrinsically drug-resistant cancers and in tumors that acquired resistance.
- Reconstituted P-glycoprotein exhibited ATPase activity, ATP-dependent drug transport, and binding of anticancer drugs and resistance-reversing agents.
- The liposome model facilitated detailed biochemical studies of P-glycoprotein function.
Conclusions:
- P-glycoprotein is implicated in both intrinsic and acquired multidrug resistance in human cancers.
- Understanding P-glycoprotein's biochemical functions is crucial for developing strategies to overcome drug resistance.
- Targeting P-glycoprotein-expressing tumor cells holds promise for future cancer therapy.