Metallothionein levels in ovarian tumours before and after chemotherapy

Abstract

Summary The metallothionein content of ovarian tumours is considerably higher than that found in normal ovaries (>100-fold differences in mean values, P <0.001). There was no difference between the metallothionein content of tumours from patients who had completed chemotherapy, usually with a regimen containing a platinum drug, and tumours from untreated patients. Similarly, the level of metallothionein was not influenced by response (Andrews et al., 1987). The contribution of these mechanisms to clinical resistance is not known.The metallothioneins are a range of low molecular weight (6-7 kD) proteins involved in zinc homeostasis and heavy metal detoxification (Karin & Richards, 1984). The proteins are rich in sulphydryl groups and are therefore excellent candidates for attacks by electrophiles (such as the platinum drugs). Platinum has been shown to be bound to the metallothionein fraction isolated from cells treated with cisplatin (Endresen et al., 1984). Metallothionein levels have also been associated with resistance to some alkylating agents, although the proposed mechanism advances a role for these proteins as cofactors or regulatory elements in the repair process, rather than as direct chemical scavengers (Kaina et al., 1990).There remains uncertainty as to whether data describing mechanisms of resistance in vitro is relevant to human tumours. This work describes the investigation of metallothionein levels in tumour samples obtained either before chemotherapy (initial debulking) or following combination chemotherapy (second look laparotomy). The study was designed to determine whether any gross change in metallothionein levels occurred following chemotherapy. Metallothionein levels were also measured in normal ovaries. carboplatin (300 mg m2) + cyclophosphamide (600 mg m2) alternating with ifosfamide (5 g m2) + adriamycin (50 mg m-2) at 4 week intervals for six cycles (n = 9); single agent cisplatinum (100 mg m2) once every 4 weeks for six cycles (n = 4); carboplatin (400 mg m-2) once every 4 weeks for six cycles (n = 2); melphalan (1Omg day-' for 5 days, over six cycles at 5 weeks intervals) (n = 2). Materials and methods

Cisplatin: mode of cytotoxic action and molecular basis of resistance

“…It is not unexpected, therefore, that increases in metallothionein, up to fivefold over basal levels, have been observed in cisplatin-resistant murine and human tumor models (Kelley et al, 1988;Kasahara et al, 1991). It is noteworthy that in some studies, changes in metallothionein levels in resistant cell lines, or in human ovarian tumor biopsies taken before and after cisplatinbased therapy, have not been observed (Andrews et al, 1987;Schilder et al, 1990;Murphy et al, 1991). These variations in the reported data again emphasize the multifactorial nature of resistance and also that the increase in metallothionein is not necessarily an absolute requirement for cells to attain the resistance phenotype.…”

Metallothionein expression in ovarian cancer in relation to histopathological parameters and molecular markers of prognosis

“…Nevertheless, previous studies that directly examined response to chemotherapy by second-look laparotomy also did not find a relation between MT expression and response to chemotherapy. 18,19 Besides the reported correlation of MT expression with histological grade and a borderline significant trend with FIGO stage, MT did not correlate with other histopathological parameters, e.g., histological type, estrogen or progesterone receptor status and residual disease after surgery. No significant difference in MT expression was observed between 151 primary ovarian carcinomas and 38 recurrences.…”

“…For instance, MT over-expression in bladder cancer has been associated with poor response to cisplatin, 16,17 whereas no relation between MT expression and response to chemotherapy was observed for ovarian cancer, 18,19 though the most objective parameter for success of therapy, survival time, was not analyzed in these studies.…”

Metallothionein expression in human breast cancer

“…Recently, metallothionein has been found to be elevated in neoplastic cells (Murphy et al, 1991) and overexpression has been found to confer resistance to radiotherapy (Thornally and Vasak 1985;Renan and Dowman, 1989) and chemotherapeutic agent toxicity (Andrews et al,1987;Kelley et al, 1988;Webber et al, 1988;Kaina et al, 1990), although this has been disputed (Schilder et al, 1990;Murphy et al, 1991). Metallothionein overexpression has been described in human breast carcinoma and appears to be associated with a poorer prognosis (Fresno et al, 1993;Schmid et al, 1993 (Page and Anderson, 1987;Ellis et al, 1992) Sections 3 ,um thick were also cut and used for immunohistochemical staining of metallothionein according to a standard ABC method.…”