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Genetic chemoprotection with mutant O6-alkylguanine-DNA-alkyltransferases
1CRC Gene Therapy Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK.
Abstract:
One of the main barriers to more efficacious use of modern chemotherapeutic agents, is the collateral toxicity exhibited in normal, highly proliferative tissues, primarily the haemopoietic, gastrointestinal and pulmonary tissues. Drug resistance of tumours to these drugs compounds this problem. This review discusses the role of O6-alkylguanine-DNA alkyltransferase (ATase) in conferring protection against O6-alkylating agents in normal tissue, focusing mainly on the haemopoietic compartment. The development of mutant forms of ATase, which are resistant to the effects of soluble analogues of O6-alkylation such as O6-benzylguanine, is examined and the gene therapy approach of combining these two strategies to confer chemoprotection to vulnerable tissues whilst sensitising malignant tissue is reviewed.
Insights
This review explores how O6-alkylguanine-DNA alkyltransferase (ATase) protects normal tissues from chemotherapy. It examines mutant ATase forms and gene therapy to shield healthy cells while sensitizing tumors to alkylating agents.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapeutic agents cause collateral toxicity in normal tissues like hematopoietic, gastrointestinal, and pulmonary systems.
- Tumor drug resistance further complicates the efficacy of chemotherapy.
- O6-alkylguanine-DNA alkyltransferase (ATase) plays a crucial role in protecting normal tissues from O6-alkylating agents.
Purpose of the Study:
- To review the protective role of ATase in normal tissues, particularly the hematopoietic compartment, against O6-alkylating agents.
- To examine the development and function of mutant ATase forms resistant to O6-alkylation analogues.
- To discuss the potential of gene therapy combining ATase strategies for chemoprotection and tumor sensitization.
Main Methods:
- Review of existing literature on ATase function and O6-alkylating agents.
- Analysis of studies on mutant ATase development and resistance mechanisms.
- Examination of gene therapy approaches for chemoprotection.
Main Results:
- ATase confers protection against O6-alkylating agents in normal tissues.
- Mutant ATase forms exhibit resistance to O6-alkylation analogues like O6-benzylguanine.
- Gene therapy strategies can potentially confer chemoprotection to normal tissues and sensitize tumors.
Conclusions:
- Targeting ATase offers a promising strategy for mitigating chemotherapy-induced toxicity.
- Development of resistant ATase mutants and gene therapy holds potential for improved cancer treatment outcomes.
- Combining chemoprotective and tumor-sensitizing approaches via ATase modulation could enhance therapeutic efficacy.