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P-glycoprotein expression in primary and metastatic malignant melanoma
D Schadendorf1, R Herfordt, B M Czarnetzki
1University Hospital Rudolf Virchow, Department of Dermatology, FU Berlin, Germany.
Abstract:
Metastatic malignant melanoma is notoriously resistant to chemotherapeutic agents, but the exact mechanisms involved in this drug resistance are unknown. One recently defined major mechanism of multidrug resistance involves the overexpression of P-glycoprotein on cell membranes. In order to evaluate the significance of this putative drug efflux pump for chemoresistance of malignant melanoma, five different antibodies were employed to examine P-glycoprotein expression on tissue from 33 primary malignant melanomas and 35 metastases, before and after chemotherapy, using immunohistological techniques. The expression of P-glycoprotein was low on primary cutaneous melanomas (three of 33), and on metastases (one of 35). Normal tissue in and around the melanoma showed reactivity of endothelial cells, stromal cells and eccrine sweat glands with several antibodies tested. Chemotherapy with drugs commonly used in metastatic melanoma, including agents known to induce P-glycoprotein expression in other tumours (vindesine, cisplatin) had no effect on P-glycoprotein expression in human melanoma metastases. The high chemoresistance of human melanoma cells in vitro and in vivo is probably not mediated via P-glycoprotein, and other possible mechanisms involved will have to be explored in future studies.
Insights
P-glycoprotein (P-gp) does not appear to cause drug resistance in malignant melanoma. Studies show low P-gp expression in melanoma tissues, unaffected by chemotherapy, suggesting other resistance mechanisms are at play.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Metastatic malignant melanoma exhibits significant resistance to chemotherapy.
- P-glycoprotein (P-gp) overexpression is a known mechanism of multidrug resistance in various cancers.
- The role of P-gp in melanoma chemoresistance remains unclear.
Purpose of the Study:
- To investigate the significance of P-glycoprotein expression in chemoresistance of malignant melanoma.
- To evaluate P-gp levels in primary and metastatic melanoma tissues before and after chemotherapy.
Main Methods:
- Immunohistological techniques using five different antibodies to detect P-gp expression.
- Analysis of tissue samples from 33 primary melanomas and 35 metastases.
- Assessment of P-gp expression before and after chemotherapy with agents like vindesine and cisplatin.
Main Results:
- P-glycoprotein expression was found to be low in both primary melanomas (3/33) and metastases (1/35).
- Chemotherapy did not alter P-gp expression levels in melanoma metastases.
- Normal tissues showed varying P-gp reactivity in endothelial cells, stromal cells, and sweat glands.
Conclusions:
- P-glycoprotein is unlikely to be the primary mediator of chemoresistance in human melanoma.
- Further research is needed to identify other mechanisms contributing to melanoma drug resistance.