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Impairments in antifolate transport are common in retinoblastoma tumor samples
Richard G Gorlick1, David H Abramson, Rebecca Sowers
1Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Background:
Many patients with retinoblastoma have a genetic predisposition to cancer and external beam radiation therapy and alkylating agent chemotherapy may increase their risk of secondary malignancy. Identification of effective chemotherapy agents for retinoblastoma that are not associated with an elevated risk of secondary malignancy would be beneficial.
Procedure:
Twenty-six specimens of fresh retinoblastoma tumor cells were studied in vitro with a PT430 competitive displacement assay. Differential displacement of the PT430 by methotrexate and not trimetrexate was considered indicative of a defect in reduced folate carrier (RFC)-mediated transport. Elevations in the accumulation of PT430 were considered indicative of dihydrofolate reductase (DHFR) amplification.
Results:
In 9 of the 26 (35%) samples, displacement by methotrexate was less than half the displacement by trimetrexate indicative of a defect in the RFC. In 5 of the 26 (19%) samples, trimetrexate did not displace the PT430. In 7 of 26 (27%) samples, the peak PT430 accumulation was suggestive of DHFR overexpression. Overall 9 of 26 (35%) samples had no evidence of a transport defect or DHFR overexpression and would be anticipated to be potentially sensitive to methotrexate. In 15 of the 26 (58%), no defects existed in trimetrexate displacement or DHFR overexpression and would be anticipated to be potentially sensitive to trimetrexate.
Conclusion:
These results would support consideration of a phase II study to determine the effectiveness of trimetrexate for recurrent intra-ocular retinoblastoma.
Insights
Trimetrexate may be an effective chemotherapy for retinoblastoma, potentially offering a safer alternative to traditional treatments. This study investigated its efficacy by examining drug transport and enzyme activity in tumor cells.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Retinoblastoma patients often have genetic predispositions to cancer.
- Current treatments like radiation and chemotherapy increase secondary malignancy risk.
- Safer chemotherapy agents for retinoblastoma are needed.
Purpose of the Study:
- To evaluate the potential of trimetrexate as a chemotherapy agent for retinoblastoma.
- To assess the mechanisms of action for methotrexate and trimetrexate in retinoblastoma cells.
Main Methods:
- In vitro study of 26 retinoblastoma tumor cell specimens.
- Used PT430 competitive displacement assay to analyze drug transport.
- Assessed reduced folate carrier (RFC) function and dihydrofolate reductase (DHFR) amplification.
Main Results:
- Defects in RFC-mediated transport were found in 35% of samples.
- DHFR overexpression was suggested in 27% of samples.
- 58% of samples showed potential sensitivity to trimetrexate, with no identified transport defects or DHFR overexpression.
Conclusions:
- Findings support further investigation into trimetrexate's effectiveness.
- Trimetrexate shows promise for treating recurrent intra-ocular retinoblastoma.
- Phase II study of trimetrexate is recommended.
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