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Alkylating agents and platinum: is clinical resistance simply a tumor cell phenomenon?
1Section of Genitourinary Cancer, National Cancer Institute, Bethesda, MD 20892.
Abstract:
Alkylating agents and platinum compounds comprise a large group of drugs that may exhibit marked differences in pharmacologic properties on the subcellular and clinical levels. Studies of the subcellular pharmacology of individual agents in this group suggest that cellular resistance to these drugs as a class may be modulated at three general levels: transmembrane drug accumulation, cytosolic inactivation of drug, and altered DNA repair. Traditionally, one unspoken assumption of cancer chemotherapy has been that in vitro tumor cell resistance equates with clinical resistance. Recent studies of platinum DNA adduct in nonmalignant tissues from cancer patients actively receiving therapy suggest that this assumption should be reassessed. In studies of platinum-DNA adduct from four different groups (using four different methods to assess adduct levels in nonmalignant tissues), the relationship between adduct level and disease response is a direct one; ie, the higher the adduct level, the better the clinical response to therapy. Here the data are reviewed that suggest that clinical resistance to DNA-damaging agents is not simply a tumor cell phenomenon and may represent the pharmacogenetic ability of individuals to protect cellular DNA.
Insights
Clinical resistance to DNA-damaging chemotherapy drugs like alkylating agents and platinum compounds may depend on an individual's genetic ability to protect their DNA, not just tumor cell resistance.
Area of Science:
- Pharmacology
- Oncology
- Genetics
Background:
- Alkylating agents and platinum compounds are key chemotherapy drugs with varying pharmacologic effects.
- Cellular resistance to these drugs can occur via drug accumulation, inactivation, or DNA repair mechanisms.
Purpose of the Study:
- To reassess the assumption that in vitro tumor cell resistance predicts clinical resistance to chemotherapy.
- To investigate the relationship between DNA adduct levels in nonmalignant tissues and clinical response to DNA-damaging agents.
Main Methods:
- Review of studies assessing platinum-DNA adduct levels in nonmalignant tissues from cancer patients.
- Utilized four different methods across four distinct study groups to measure adduct levels.
Main Results:
- A direct correlation was observed between platinum-DNA adduct levels and clinical response.
- Higher adduct levels in nonmalignant tissues corresponded to better therapeutic outcomes.
Conclusions:
- Clinical resistance to DNA-damaging agents may not solely be a tumor cell characteristic.
- Individual pharmacogenetic ability to protect cellular DNA might play a significant role in treatment response and resistance.