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Genetic basis of drug sensitivity in human testis tumour cells
X Wang1, M Hafezparast, J R Masters
1Institute of Urology and Nephrology, University College of London, United Kingdom.
Abstract:
Testicular germ cell tumours (TGCT) are cured in over 80% of patients by using combination chemotherapy. However, the mechanism regulating this sensitivity has not been defined. Because cells derived from patients with DNA repair syndromes are similar to TCGT in their sensitivity to certain DNA-damaging agents and some of the genes involved have been cloned by functional complementation, the purpose of our study was to determine whether drug sensitivity in TGCT also has a genetic basis. Three testis tumour cell lines (cisplatin-sensitive) and 3 bladder cancer cell lines (cisplatin-resistant) were fused with a cisplatin-sensitive cell line (D98orC1). The authenticity of the hybrids was confirmed by karyotyping and PCR analysis of locus-specific sites, and sensitivities to cisplatin were measured by colony forming assays. The hybrids between sensitive cell lines were more resistant to cisplatin than the parental cells, indicating that functional complementation had occurred. The hybrids between the cisplatin-resistant and sensitive cells were intermediate in their cisplatin sensitivity, indicating that resistance is incompletely dominant. We conclude that cisplatin sensitivity has a genetic basis in TGCT and that resistance to cisplatin can be conferred by somatic cell fusion. Our data indicate that gene(s) controlling sensitivity to chemotherapy in TGCT might be identified by expression cloning.
Insights
Chemotherapy sensitivity in testicular germ cell tumours (TGCT) has a genetic basis. Somatic cell fusion experiments suggest genes controlling drug sensitivity can be identified, potentially improving TGCT treatment.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Testicular germ cell tumours (TGCT) show high cure rates (>80%) with combination chemotherapy.
- The underlying mechanisms of chemotherapy sensitivity in TGCT remain largely undefined.
- Similarities in DNA-damaging agent sensitivity between TGCT and DNA repair syndromes suggest a potential genetic basis.
Purpose of the Study:
- To investigate if drug sensitivity in TGCT is genetically determined.
- To explore the role of genetic factors in cisplatin sensitivity in testicular cancer.
Main Methods:
- Somatic cell fusion was employed, combining cisplatin-sensitive TGCT lines with cisplatin-resistant bladder cancer lines.
- Hybrid cell line authenticity was verified using karyotyping and PCR analysis.
- Cisplatin sensitivity was quantitatively assessed through colony-forming assays.
Main Results:
- Hybrids formed from fusions between sensitive cell lines exhibited increased cisplatin resistance, indicating functional complementation.
- Hybrids resulting from fusions between resistant and sensitive cells displayed intermediate cisplatin sensitivity, suggesting incomplete dominance of resistance.
- Somatic cell fusion can confer resistance to cisplatin in TGCT.
Conclusions:
- Cisplatin sensitivity in TGCT is underpinned by a genetic basis.
- Genes governing chemotherapy sensitivity in TGCT may be discoverable through expression cloning techniques.
- These findings open avenues for identifying novel therapeutic targets in testicular cancer treatment.