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Role of metallothionein in cisplatin sensitivity of germ-cell tumours
C Meijer1, A Timmer, E G De Vries
1Department of Medical Oncology, University Hospital, Groningen, The Netherlands. j.meijer@int.azg.nl
Abstract:
Cisplatin (CDDP) is an extremely active drug in the treatment of germ-cell tumours. Earlier, we found an unexpected inverse correlation between the total amount of sulfhydryl groups and CDDP sensitivity in a panel of 3 human germ-cell-tumour and 3 colon-carcinoma cell lines. Major components of the sulfhydryl groups are glutathione and metallothionein (MT). We further investigated a possible role of MT in the CDDP sensitivity of germ-cell tumours. MT levels and functionality of the germ-cell-tumour and colon-carcinoma cell lines were found to be inversely correlated with CDDP sensitivity. No difference in sub-cellular localization of MT could be observed among the types of cell lines. In agreement with the in vitro data, immunohistochemical detection of MT was high in 11/14 primary human germ-cell tumours and low in 7/7 human colon carcinomas. MT-protein expression in primary germ-cell tumours did not discriminate between responding and non-responding patients. As compared with the primary tumours, MT-protein expression decreased in 5/7 post-chemotherapy residual vital tumours or remained undetectable (2/7). MT-protein expression in the germ-cell tumours was not related to total p53-protein expression. In summary, over-expression of MT was found in germ-cell tumours, both in cell lines and in human tumours. Although MT-protein over-expression seems to be associated with the CDDP sensitivity of germ-cell tumours, MT-protein expression in primary germ-cell tumours did not differ between responding and non-responding patients and therefore cannot be used to predict response to chemotherapy.
Insights
Metallothionein (MT) is overexpressed in germ-cell tumours, inversely correlating with cisplatin (CDDP) sensitivity. However, MT levels in primary tumours do not predict patient response to CDDP chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cisplatin (CDDP) is a key chemotherapeutic agent for germ-cell tumours.
- Previous studies indicated an inverse correlation between sulfhydryl groups and CDDP sensitivity.
- Metallothionein (MT) is a major component of cellular sulfhydryl groups.
Purpose of the Study:
- To investigate the role of metallothionein (MT) in cisplatin (CDDP) sensitivity in germ-cell tumours.
- To compare MT levels and functionality in germ-cell tumour and colon carcinoma cell lines.
- To evaluate MT expression in primary and post-chemotherapy human tumours.
Main Methods:
- Cultured human germ-cell tumour and colon carcinoma cell lines were analyzed for MT levels and functionality.
- Immunohistochemistry was used to detect MT-protein expression in primary and residual human tumours.
- Correlation analysis was performed between MT expression, CDDP sensitivity, and patient response.
Main Results:
- MT levels and functionality were inversely correlated with CDDP sensitivity in cell lines.
- MT expression was significantly higher in primary germ-cell tumours compared to colon carcinomas.
- MT expression in primary germ-cell tumours did not predict patient response to chemotherapy and decreased after treatment.
Conclusions:
- Metallothionein (MT) is overexpressed in germ-cell tumours and associated with in vitro CDDP sensitivity.
- MT expression in primary germ-cell tumours cannot predict patient response to cisplatin (CDDP) chemotherapy.
- MT levels decrease post-chemotherapy, suggesting a role in drug resistance or tumour response.
