Treatment of Metastatic Malignant Melanoma with Dacarbazine plus Tamoxifen

Cocconi, Giorgio; Bella, Mariangela; Calabresi, F.; Tonato, Maurizio; Canaletti, R; Boni, C.; Buzzi, Franco; Ceci, Guido; Corgna, E.; Costa, Paolo; Lottici, Renata; Papadia, Franco; Sofra, Maria; Bacchi, M.

doi:10.1056/nejm199208203270803

Cited by 230 publications

(112 citation statements)

References 39 publications

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“…Findings with tamoxifen and 173-oestradiol are particularly interesting in view of the recent reported benefit of tamoxifen in combined chemotherapy regimens (Cocconi et al, 1992) and epidemiological data supporting a female survival benefit in metastatic melanoma (Vossaert et al, 1992;Stidham et al, 1994;Garbe et al, 1995;Karakousis and Driscoll, 1995).…”

Section: Discussionmentioning

confidence: 98%

“…Currently, the most promising approaches involve combined chemotherapy in which DNA-damaging agents, such as cisplatin, carmustin and dacarbazine, are administered with tamoxifen. Results to date suggest that tamoxifen has little to offer as a single-agent therapy compared with other agents already in use; however, when it is combined with other agents, a significant extension in the diseasefree interval has been achieved for patients with advanced metastatic melanoma (Del Prete et al, 1984;McClay et al, 1989McClay et al, , 1992Buzaid et al, 1991;Cocconi et al, 1992;Fierro et al, 1993;Reintgen and Saba, 1993). It is not clear, at the time of writing, how tamoxifen works in combined chemotherapy regimens.…”

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confidence: 99%

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Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Dewhurst

Gee²,

Rennie³

et al. 1997

Br J Cancer

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Summary Invasion through stromal extracellular matrix (ECM) is part of the complex, multistep process of tumour cell invasion and metastasis. Our group has previously demonstrated that calcium and calmodulin are important in another step in the metastatic cascadethat of attachment of cells to ECM. Interestingly, the non-steroidal anti-oestrogen tamoxifen (which also has calmodulin antagonist activity), used in the treatment of breast cancer and now in metastatic cutaneous melanoma, can inhibit the attachment of normal and neoplastic cells to ECM. In this study, we investigated whether such drugs, known to inhibit cell attachment, could also subsequently reduce their invasion through a layer of human fibronectin. We examined the ability of the specific calmodulin antagonist J8, tamoxifen and its two major metabolites, N-desmethyltamoxifen (N-des) and 4-hydroxytamoxifen (4-OH), as well as the pure anti-oestrogen ICI 182,780 and 17,Boestradiol to inhibit invasion of the human cutaneous melanoma cell line, A375-SM, uveal melanoma cells and uveal melanocytes. A375-SM cells and uveal melanoma cells showed a high level of invasion (15.2% and 33.7% respectively) compared with melanocytes (around 5%) under the experimental conditions used. Submicromolar concentrations of N-des, tamoxifen, J8 and 1 7,B-oestradiol significantly reduced the invasiveness of the A375-SM cell line. The uveal melanoma cells also showed similar inhibition, although at higher concentrations of these agents. 4-OH and ICI 182, 780 had little or no effect on invasion of A375-SM cells (these were not tested on uveal melanoma cells). All cells used in this study were found to be negative for type nuclear oestrogen receptors, reinforcing the possibility that tamoxifen and 17,-oestradiol can act via mechanisms unrelated to binding to classical oestrogen receptors to inhibit tumour cell invasion.Keywords: melanoma; invasion; calmodulin antagonists; tamoxifen; oestrogen The prognosis for patients with either cutaneous (Garbe et al, 1995) or uveal melanoma (Bedikian et al, 1981;Rajpal et al, 1983) is poor once these tumours have metastasized. Metastatic spread involves several different stages and, in escaping from the primary tumour and in forming distal metastatic deposits, neoplastic cells need to attach to and subsequently invade through stromal ECM (Albini and Colacci, 1993 for review). Metastatic melanoma cells express a greater range of adhesion molecules than their non-transformed precursor, the melanocyte (Mortarini and Anichini, 1993). Initial attachment of cells to ECM proteins then leads to a reorganization of the cell cytoskeleton to form focal adhesions (Van Leeuwen et al, 1994).In recent years, our laboratory has investigated the role of signal transduction systems in the early stages of cell attachment and shown that attachment of melanoma cells to ECM proteins appears to involve intracellular signalling systems, in particular calcium and calmodulin (MacNeil et al, 1992. We also demonstrated that tamoxifen and two of its major metabolites c...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Dewhurst

Gee²,

Rennie³

et al. 1997

Br J Cancer

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“…The ERα gene promoter is also hypermethylated in other types of cancer and antiestrogen therapy benefits some cancer patients other than those with breast cancer (16)(17)(18)(19)29). In the case of melanoma, ERα gene hypermethylation strongly predicts melanoma progression, with unknown underlying molecular mechanisms (16).…”

Section: Acetylated Stat3 Is Crucial For Erα Gene Methylation In Melamentioning

confidence: 99%

Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation

Lee

Zhang

Herrmann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

205

202

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The mechanisms underlying hypermethylation of tumor-suppressor gene promoters in cancer is not well understood. Here, we report that lysine acetylation of the oncogenic transcription factor STAT3 is elevated in tumors. We also show that genetically altering STAT3 at Lys685 reduces tumor growth, which is accompanied by demethylation and reactivation of several tumor-suppressor genes. Moreover, mutating STAT3 at Lys685 disrupts DNA methyltransferase 1-STAT3 interactions in cultured tumor cells and in tumors. These observations are confirmed by treatment with an acetylation inhibitor, resveratrol. Furthermore, reduction of acetylated STAT3 in triple-negative breast cancer cells leads to demethylation and activation of the estrogen receptor-α gene, sensitizing the tumor cells to antiestrogens. Our results also demonstrate a correlation between STAT3 acetylation and methylation of estrogen receptor-α in melanoma, which predicts melanoma progression. Taken together, these results suggest a role of STAT3 acetylation in regulating CpG island methylation, which may partially explain aberrant gene silencing in cancer. These findings also provide a rationale for targeting acetylated STAT3 for chemoprevention and cancer therapy.

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“…33 In small, randomised trials that compared the dacarbazine alone and with a combined with either tamoxifen or IFN-α 2. The latter two produced higher response rate than dacarbazine alone, 14,16 but phase III ECOG trial failed to prove it. 17 Chemotherapeutic agents in various combination have been used in the treatment of stage IV patients.…”

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confidence: 99%

Malignant mucosal melanoma of the head and neck — a review

Lengyel

Gilde

Remenár

et al. 2003

Pathol. Oncol. Res.

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Treatment of Metastatic Malignant Melanoma with Dacarbazine plus Tamoxifen

Abstract: In the treatment of metastatic malignant melanoma, dacarbazine plus tamoxifen is more effective than dacarbazine alone, as indicated by both the response rate and the median survival; the difference in efficacy is among women.

Cited by 230 publications

References 39 publications

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation

Malignant mucosal melanoma of the head and neck — a review

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