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Mechanisms of multidrug resistance in cancer treatment
1Molecular Oncology Laboratory, University of Oxford, John Radcliffe Hospital, Headington, UK.
Abstract:
Advanced breast cancer responds to a range of cytotoxic agents, but resistance always develops. Understanding the mechanisms of resistance may provide new therapeutic options. There are several major groups of resistance mechanisms. 1) The multidrug resistant phenotype. This is due to a membrane pump that can extrude a wide range of anticancer drugs--the P-glycoprotein. It is inhibited by a range of clinically used calcium channel blockers such as nifedipine and verapamil. Several other membrane proteins of 180 KD, 170 KD, 300 KD and 85 KD have been reported and are associated with MDR. 2) Glutathione transferences and detoxification mechanisms. These are a multigene family of enzymes that conjugate glutathione to chemically reactive groups. There are 3 major groups of enzymes--acidic, basic and neutral. They have been implicated in resistance to doxorubicin, melphalan cisplatinum chlorambucil and other alkylating agents. Other protecting systems include metallothionein and selenium dependent glutathione peroxidase. HSP27 confers doxorubicin resistance. 3) Topoisomerase II. DNA topoisomerases are involved in several aspects of DNA metabolism in particular genetic recombination, DNA transcription, chromosome segregation. They are a target for doxorubicin, mitoxantrone, VP16. Low levels of expression are associated with resistance. However, it is oestrogen inducible and this may be of therapeutic value. A novel topo IIb which is more drug resistant has been reported. 4) DNA repair. A score or more of genes are involved in the repair of DNA damage by drugs and radiation. Defective DNA repair may predispose to cancer of the breast and be responsible for adverse radiation reactions. Enhanced repair has been shown to be a mechanism of cisplatinum resistance. Several genes are inducible by DNA damage and may confer resistance e.g. A45. 5) Drug activation. Mitomycin C as well as cyclophosphamide and VP16 require activation for their effects. Low levels of cytochrome p450 reductase are associated with MMC resistance.
Insights
Understanding breast cancer drug resistance mechanisms, including P-glycoprotein pumps, glutathione transferases, topoisomerase II, DNA repair, and drug activation, is crucial for developing new therapeutic options against advanced cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Advanced breast cancer often develops resistance to cytotoxic chemotherapy.
- Identifying resistance mechanisms is key to overcoming treatment failure and improving patient outcomes.
- Multiple molecular pathways contribute to multidrug resistance (MDR) in cancer cells.
Purpose of the Study:
- To review and elucidate the primary mechanisms of drug resistance in advanced breast cancer.
- To highlight potential therapeutic targets and strategies for overcoming chemoresistance.
Main Methods:
- Literature review of established and emerging mechanisms of multidrug resistance.
- Analysis of key molecular players involved in drug efflux, detoxification, DNA repair, and drug metabolism.
- Discussion of enzymes, proteins, and genetic factors contributing to chemoresistance.
Main Results:
- Multidrug resistance phenotype mediated by P-glycoprotein and other membrane proteins.
- Detoxification pathways involving glutathione transferases and other protective systems.
- Role of Topoisomerase II expression levels and DNA repair mechanisms in conferring resistance.
- Implications of drug activation pathways, such as cytochrome P450 reductase, in treatment efficacy.
Conclusions:
- Drug resistance in advanced breast cancer is multifactorial, involving efflux pumps, detoxification, altered DNA repair, and drug metabolism.
- Targeting these resistance mechanisms, such as inhibiting P-glycoprotein or modulating Topoisomerase II, may offer novel therapeutic strategies.
- Further research into these pathways is essential for developing more effective breast cancer treatments.