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Preclinical perspectives on platinum resistance.
1CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, England.
Drugs
|June 23, 2000
Summary
Cisplatin exerts anticancer effects by damaging DNA, but tumors can become resistant through various mechanisms. Understanding these resistance pathways aids in developing new platinum drugs to overcome resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cisplatin, a platinum-based chemotherapy drug, has been used for 30 years to treat various cancers.
- Its antitumour effects stem from DNA damage, forming adducts primarily on guanine bases.
- Tumour resistance to cisplatin is a significant clinical challenge, necessitating a deeper understanding of its mechanisms.
Purpose of the Study:
- To review the mechanisms by which cisplatin exerts its antitumour effects.
- To elucidate the diverse mechanisms of cisplatin resistance in tumour cells.
- To highlight how understanding resistance pathways informs the development of novel platinum analogues.
Main Methods:
- Review of laboratory studies on cisplatin's mechanism of action and resistance.
- Analysis of in vitro models of cisplatin resistance using repeatedly exposed tumour cells.
- Examination of genetic and molecular alterations associated with cisplatin sensitivity and resistance.
Main Results:
- Cisplatin forms intrastrand and interstrand DNA adducts, with intrastrand guanine adducts being most common.
- Resistance mechanisms include reduced DNA damage (decreased uptake, thiol inactivation) and post-damage effects (altered DNA repair, apoptosis evasion).
- Defective nucleotide excision repair (NER) can lead to hypersensitivity, while increased NER or loss of mismatch repair (MMR) can cause resistance.
Conclusions:
- Cisplatin's efficacy is linked to DNA adduct formation, but resistance mechanisms are multifaceted.
- Understanding resistance pathways, including DNA repair and apoptosis regulation, is crucial for improving cancer therapy.
- Knowledge of these pathways has driven the development of new platinum drugs designed to circumvent resistance, with promising clinical trial results.