We and others have found, in phase II trials, that the addition of tamoxifen (TAM) to cisplatin-containing regimens markedly increases the response rate of malignant melanoma. Patients treated with TAM plus DDP-containing regimens have an objective response rate of 50%, with a complete response rate of 20%; without TAM the response rate is 10%. It is our hypothesis that it is the interaction of TAM with DDP that is responsible for this improved response rate. The first specific aim of this research program is to confirm the ability of TAM to enhance DDP sensitivity in patients with malignant melanoma. We will conduct a clinical trial (TAMOPLAT) in which patients failing DDP will receive DDP plus TAM.
The second aim i s to quantitate those parameters known to be determinants of DDP and TAM sensitivity on fresh tissue samples from melanoma patients and seek correlations with in vivo and in vitro DDP sensitivity. This will involve measurements of estrogen receptor content, DDP sensitivity by colony forming assay, GSH content, expression of metallothionein II, drug uptake, both intra- and interstrand crosslink formation, and expression of the H-ras gene. In addition needle biopsies will be obtained 24 hours after treatment with DDP alone and DDP/TAM for determination of DDP DNA adduct formation by histochemical staining.
The third aim i s to determine the basic mechanism(s) of DDP resistance in melanoma, and to investigate techniques by which DDP sensitivity can be enhanced in this disease. We will investigate: a) the rate at which DDP resistance develops using human xenografts; b) the mechanism(s) by which TAM enhances DDP sensitivity; c) the role of protein kinases A and C in modulating DDP sensitivity; and d) the ability to augment sensitivity using growth factors to which melanoma cells respond. The major factors determining DDP resistance in vitro are now well known, and the stage is well set for this multidisciplinary attack on the problem of DDP resistance in melanoma.
