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Tumor heterogeneity, tumor size, and radioresistance
1Department of Radiation Medicine, University of Kentucky Medical Center, Lexington 40536-0084.
Abstract:
Mutant clonogenic cells, resistant to individual chemotherapeutic agents, are known to play a central role in clinical chemotherapy failure. The possibility that mutant cells, resistant to conventionally fractionated megavoltage photon radiotherapy, exist in human tumors is considered. Applying the mutation theory of Luria and Delbruck to describe the appearance of resistant cells, several conclusions follow: (a) the mean number of resistant cells in a tumor will be determined by the tumor size and the mutation rate; (b) a wide variation in radiosensitivity in tumors of the same histology is expected, because of a large variation in the number of resistant cells that they contain; (c) the presence of a resistant clone will not reduce the tumor-control probability until the tumor becomes sufficiently large; (d) initial response will not be a reliable predictor of long-term control; (e) clonogenic assays may not accurately predict treatment outcomes; (f) the mutation rate may be the most accurate predictor of tumor aggressiveness and resistance to various treatment modalities; (g) tumors with a low mutation rate, which may include seminoma, Hodgkin's disease and many pediatric tumors would be curable by either chemotherapy or radiation; (h) pleomorphic tumors with a high mutation rate, which may include glioblastoma multiforme, would be difficult to cure by any means. Clinical and experimental evidence is reviewed for the existence of radioresistant cell lines in human and animal tumors, and further experiments are proposed to test this hypothesis. Treatment strategies for targeting radioresistant clones are discussed.
Insights
The study suggests that radioresistant mutant cells, arising from a tumor's mutation rate, significantly impact treatment outcomes. Understanding this mutation rate is key to predicting tumor aggressiveness and treatment success for various cancers.
Area of Science:
- Oncology
- Radiation Oncology
- Cancer Biology
Background:
- Chemotherapy failure is often linked to mutant clonogenic cells resistant to drugs.
- The existence of radioresistant mutant cells in human tumors, similar to chemoresistance, is hypothesized.
- The Luria-Delbruck mutation theory provides a framework for understanding the emergence of resistant cell populations.
Purpose of the Study:
- To explore the implications of radioresistant mutant cells in human tumors.
- To apply mutation theory to predict tumor behavior and treatment response.
- To discuss potential treatment strategies targeting radioresistant clones.
Main Methods:
- Theoretical application of the Luria-Delbruck mutation theory to radiotherapy.
- Review of existing clinical and experimental evidence for radioresistant cell lines.
- Proposal of further experiments to validate the hypothesis.
Main Results:
- Tumor size and mutation rate determine the number of resistant cells.
- High variation in radiosensitivity is expected due to differing numbers of resistant cells.
- Initial tumor response is not a reliable predictor of long-term control; mutation rate is a better indicator of aggressiveness.
Conclusions:
- The mutation rate is a critical factor in tumor aggressiveness and resistance to therapy.
- Tumors with low mutation rates (e.g., seminoma, pediatric tumors) may be curable.
- Highly pleomorphic tumors with high mutation rates (e.g., glioblastoma) present significant treatment challenges.