Metallothionein in testicular germ cell tumors and drug resistance: Clinical correlation

Chin, Joseph L.; Banerjee, Diponkar; Kadhim, Salam; Kontozoglou, Theodosios; Chauvin, Peter J.; Cherian, M. George

doi:10.1002/1097-0142(19931115)72:10<3029::aid-cncr2820721027>3.0.co;2-6

Cited by 61 publications

(42 citation statements)

References 19 publications

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“…In stage IV melanoma patients, anticancer drugs, as well as irradiation therapy, are known to often show only a humbled rate of clinical responses. These therapeutic failures may partially be related to an enhanced MT overexpression in tumour cells, although the involvement of MT in conferring resistance to chemotherapeutics still remains under discussion (Chin et al, 1993;Hishikawa et al, 1997;Okazaki et al, 1998;Cherian et al, 2003). As a variety of endogenous factors (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…As far as we know, MT are involved in many physiological and pathophysiological processes such as the intracellular storage, transport and metabolism of heavy metal ions; they regulate essential trace metal homeostasis and play a protective role in heavy metal detoxification reactions (Miles et al, 2000;Simpkins, 2000). They can protect cells against UV-/ionic radiation (Hansen et al, 1997;Hanada et al, 1998;Reeve et al, 2000) as well as cytotoxic alkylating agents including chemotherapeutics (Chin et al, 1993;Hishikawa et al, 1997;Okazaki et al, 1998;Sunada et al, 2005), modulate oxygen free radicals and nitric oxide and inhibit apoptosis (Tsangaris and Tzortzatou-Stathopoulou, 1998). The synthesis of MT is induced by group II heavy metal ions as well as by endogenous factors such as glucocorticoids, cytokines (interleukin (IL)-1 or IL-6, interferon g (IFNg), tumour necrosis factor a (TNF-a)) or vitamin D 3 (Karin et al, 1985;Karasawa et al, 1987;Schroeder and Cousins, 1990;Sato and Sasaki, 1992;Nishimura et al, 2000).…”

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Metallothionein – overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients

et al. 2006

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Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. In the last decades, it was shown that MT overexpression in a variety of cancers is associated with resistance to anticancer drugs and is combined with a poor prognosis. In this prospective study, we examined the role of MT overexpression in melanoma patients as a prognostic factor for progression and survival. Between 1993 and 2004, 3386 patients with primary cutaneous melanoma were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. In all, 1270 patients could be followed up for further statistical analysis (Fisher's exact test, Mantel -Haenszel w 2 test, Kaplan -Meier curves). The MT data of disease-free interval and overall survival were compared univariately and multivariately in Cox regression analysis. Immunohistochemical overexpression of MT in tumour cells of patients with primary melanoma (310 of 1270; 24.4%) was associated with a higher risk for progression (117 of 167; 70.1%) and reduced survival (80 of 110; 72.7%) of the disease (Po0.0001). Similarly, Kaplan -Meier curves gave highly significant disadvantages for the MT-positive group. Univariate analysis (relative risk 7.4; 95% confidence interval (CI) 5.2 -10.2; Po0.0001 for progression; relative risk 7.1; 95% CI 4.7 -10.9; Po0.0001 for survival), as well as multivariate analysis with other prognostic markers resulted in MT overexpression as a highly significant and independent factor for prognosis in primary melanoma.

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Metallothionein – overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients

et al. 2006

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“…Tumour MT level also has been reported to correlate with resistance to anticancer reagents (Kelley et al, 1988;Kasahara et al, 1991;Chin et al, 1993;Kondo et al, 1995;Hishikawa et al, 1997). In oesophageal SCC, we already reported that MT protein expression might be a significant determinant of prognosis, in particular, associated with cisplatin resistance (Hishikawa et al, 1997).…”

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Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus

et al. 1999

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Squamous cell carcinoma (SCC) of the oesophagus is well recognized for its aggressive biological behaviour, in respect of local infiltration and metastases to regional lymph nodes and distant organs (Orrigner, 1997). Extra-oesophageal tumour spread is present in 70% of cases at the time of diagnosis, and the 5-year survival is only 3% when lymph node metastases are present, compared with 42% in lymph node negative patients (Orrigner, 1997). Patients with distant metastasis also have a poor prognosis, with a 5-year survival rate of 5% or less (Mandard et al, 1984;Orrigner, 1997).Metastasis is a multistep process involving complex associations of tumour cells with host cells or with matrix (Stracke and Liotta, 1995). Recently, genetic mechanisms underlying metastasis and pathogenesis of oesophageal SCC have been explored in several studies: int-2/hst-1 co-amplification correlated with high incidence of metastasis in distant organs (Kitagawa et al, 1991), loss of heterozygosity of the DCC gene associated with the degree of lymph node metastasis (Miyake et al, 1994), and mutation of the p53 gene in the pathogenesis (Hollstein et al, 1990;Meltzer et al, 1991) of SCC. However, there are only a limited number of reports on the prognostic indicators for invasion and metastasis of oesophageal SCC.Metallothioneins (MTs) have been described in most vertebrate and invertebrate species as low molecular weight proteins. Overexpression of MT was described in a variety of human tumours, in relation to different stages of tumour development and progression (Jasani and Schmid, 1997). MT was considered as a potential prognostic marker in invasive ductal carcinoma of the breast by Schmid et al (1993) and others (Fresno et al, 1993;Goulding et al, 1995, Oyama et al, 1996. In skin carcinoma (Zelger et al, 1994), melanoma (Zelger et al, 1993), cervical carcinoma (Lim et al, 1996) and pancreatic carcinoma (Ohshio et al, 1996), MT overexpression appears to be predominantly associated with more advanced, highly malingant tumours. To the contrary, Öfner et al (1994) reported that MT overexpression in colorectal carcinoma was associated with better clinical outcome and tumour stages. Therefore, MT overexpression may be paradoxically associated in some tumours with better clinical outcome.Tumour MT level also has been reported to correlate with resistance to anticancer reagents (Kelley et al, 1988;Kasahara et al, 1991;Chin et al, 1993;Kondo et al, 1995;Hishikawa et al, 1997). In oesophageal SCC, we already reported that MT protein expression might be a significant determinant of prognosis, in particular, associated with cisplatin resistance (Hishikawa et al, 1997). Patients with MT protein-negative tumours survived longer when treated with cisplatin than those with MT protein-positive tumours. However, the exact biological significance of the expression of MT protein and mRNA is largely unknown in the clinical setting of oesophageal SCC.Therefore, in the present study, we have investigated the expressions of both MT mRNA and its protein in...

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“…MTs appear to have a physiological role in the absorption, transport and metabolism of important trace metals, as well as a role in heavy metal detoxification. MTs have also been shown to affect the cellular sensitivity to cisplatinum (Bahnson et al, 1991; Kasahara et al, 1991;Chin et al, 1993;Kondo et al, 1995). No previous studies have reported on MT expression in OS.…”

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P-glycoprotein and metallothionein expression and resistance to chemotherapy in osteosarcoma

Shnyder¹,

Hayes²,

Pringle³

et al. 1998

Br J Cancer

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Summary The expression of the drug resistance (DR) mediators P-glycoprotein (P-gp) and the metallothioneins (MT) was assessed immunohistochemically in biopsy material from patients with high-grade malignant osteosarcoma (OS). No significant difference was found in survival rate between expressors of both P-gp and MT and non-expressors. Thus, it was concluded that lack of expression of these two drug resistance-related proteins does not appear to confer any advantage in terms of patient survival in osteosarcoma.Keywords: osteosarcoma; P-glycoprotein; metallothioneins; drug resistance; immunohistochemistry; confocal laser scanning microscopy Failure to respond to, or relapse from, drug therapy are among the most common causes of death in patients with osteosarcoma (OS). Tumour unresponsiveness to drug therapy may be related to many factors. The most frequently described model of drug resistance is the P-glycoprotein (P-gp)-specific multiple-drug resistance (MDR) gene phenotype (Juliano and Ling, 1976). Increased levels of P-gp are thought to confer MDR to tumour cells by decreasing the net intracellular accumulation of unrelated lipophilic cytotoxic agents, such as doxorubicin and vincristine (Weinstein et al, 1990), which are commonly used in treatment regimens for high-grade malignant OS. Results from earlier studies carried out on OS have been conflicting. While some have shown a correlation between Pgp expression at biopsy, and response to therapy (Chan et al, 1991; Wunder et al, 1993), other groups have shown that it is possible for OS cells to be P-gp negative, but still be drug resistant (Shnyder et al, 1994;Kandel et al, 1995).Various mechanisms for drug resistance due to the exclusion from cells of cisplatinum, which is also commonly used in therapy for OS, have also been proposed (Richon et al, 1987;Andrews and Howell, 1990). One such mechanism proposes the involvement of metallothioneins (MTs), which are intracellular cytoplasmic proteins containing high amounts of thiol groups as well as being rich in cysteine. These thiol groups are able to bind to several cytotoxic agents containing heavy metals (Thiele et al, 1986), such as cisplatinum. MTs appear to have a physiological role in the absorption, transport and metabolism of important trace metals, as well as a role in heavy metal detoxification. MTs have also been shown to affect the cellular sensitivity to cisplatinum (Bahnson et al, 1991; Kasahara et al, 1991;Chin et al, 1993;Kondo et al, 1995). No previous studies have reported on MT expression in OS.In this study, the expression of P-gp and MT was assessed immunohistochemically in biopsy material from patients with clinically diagnosed high-grade malignant OS, and the expression Received 29 May 1996 Revised 27 January 1998 Accepted 10 February 1998Correspondence to: SD Shnyder, Department of Biochemistry, University of Otago, Box 56, Dunedin, New Zealand of these molecules was statistically analysed with respect to patient survival data (over 5 years) to determine whether there were any correla...

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Metallothionein in testicular germ cell tumors and drug resistance: Clinical correlation

Cited by 61 publications

References 19 publications

Metallothionein – overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients

Metallothionein – overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients

Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus

P-glycoprotein and metallothionein expression and resistance to chemotherapy in osteosarcoma

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