metallothionein and Germinoma

Data concerning the involvement of elevated metallothionein (MT) expression in drug resistance are obviously scattered and contrasting. The presence of the MT gene product protein was screened in 51 untreated human germ cell testicular tumours, furthermore a relationship between MT expression and clinical resistance was investigated. Using monoclonal antibody and immunoenzyme staining elevated MT level could be demonstrated in nuclei and cytoplasm of both seminomas and non seminomatous germ cell testis tumours. Thirty-one tumours (61%) showed extensive, 15 (29%) focal positive staining. In contrast teratomas expressed this antigen negatively or scarcely. The highest level of MT was stated in early stages (I, IIA) compared with progressed stages (IIB, III) (p = 0.0004). Between the high level of MT and clinical resistance a converse correlation could be shown because the resistant tumours expressed no or low, while the sensitive tumours significantly high level of MT protein which can be used as an useful marker to identify patient subgroups sensitive to anticancer therapy, at least in testis tumours.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Embryonal; Gene Expression; Germinoma; Humans; Immunohistochemistry; Male; Metallothionein; Neoplasm Staging; Seminoma; Testicular Neoplasms

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.

Topics: Antineoplastic Agents; Cisplatin; Colonic Neoplasms; Drug Screening Assays, Antitumor; Germinoma; Humans; Immunohistochemistry; Male; Metallothionein; Testicular Neoplasms; Tumor Cells, Cultured; Tumor Suppressor Protein p53

In contrast to most other types of cancer, metastatic testicular germ cell tumours (TGCT) are cured in most patients using cisplatin-based combination chemotherapy. The biochemical mechanisms underlying this sensitivity have not been defined. Drug detoxification can modulate response to chemotherapy in vivo and in vitro, and therefore we measured levels of glutathione (GSH), glutathione-S-transferase (GST) and both constitutive and cisplatin- and dexamethasone-induced levels of metallothionein (MT) in five human testis tumour cell lines. The levels were compared with those in five human bladder cancer cell lines and two cell lines with cisplatin resistance acquired in vitro. GSH levels were relatively low in the testis tumour cell lines, as might be expected in drug-sensitive cells, and there was a 77-fold increase in GSH levels in the cisplatin-resistant testis tumour cell line. GST levels were similar in the two cell types, while metallothionein levels were relatively high in the testis tumour cell lines. These data indicate that GSH may contribute to the sensitivity of TGCT to chemotherapy, and that GSH expression may be involved in the acquisition of cisplatin resistance in these tumours.

Topics: Antineoplastic Agents; Blotting, Western; Cisplatin; Dexamethasone; Drug Resistance, Neoplasm; Germinoma; Glutathione; Glutathione Transferase; Humans; Inactivation, Metabolic; Male; Metallothionein; Testicular Neoplasms; Tumor Cells, Cultured

Metallothioneins (MT) are endogenous metalloproteins involved in the homeostasis of essential metals and detoxification of toxic metals. Some recent experimental studies suggested tumor resistance to cisdiamminedichloroplatin may be associated with overexpression of MT in the tumor.. The presence of MT in 33 primary testicular germ cell tumor specimens was assessed immunohistochemically using a rabbit polyclonal rat liver MT antibody that cross-reacted with human MT. The data were correlated with the patients' clinical course.. Seminomas stained weakly or not at all for MT, regardless of the clinical stage. Most nonseminomas stained heavily for MT. The more advanced staged nonseminomas tended to stain more heavily for MT.. In view of the considerable experimental evidence as well as some inferential clinical data involving MT in cis-diamminedichloroplatin resistance, there appears to be a role for MT in cis-diamminedichloroplatin resistance in germ cell tumors. Further studies to elucidate the role of MT in germ cell tumor chemoresistance are warranted.

Topics: Cisplatin; Drug Resistance; Germinoma; Humans; Immunohistochemistry; Male; Metallothionein; Neoplasm Staging; Testicular Neoplasms