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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA052151-01
Application #
3196925
Study Section
Special Emphasis Panel (SRC (55))
Project Start
1990-05-01
Project End
1993-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Mc Clay, E F (2000) The effects of Delta(12)-PGJ(2) on malignant cells. Prostaglandins Other Lipid Mediat 62:75-90
McClay, E F; McClay, M E; Monroe, L et al. (2000) The effect of tamoxifen and cisplatin on the disease-free and overall survival of patients with high risk malignant melanoma. Br J Cancer 83:16-21
Mc Clay, E F; Mc Clay, M E (1996) Systemic chemotherapy for the treatment of metastatic melanoma. Semin Oncol 23:744-53
Jekunen, A P; Hom, D K; Alcaraz, J E et al. (1994) Cellular pharmacology of dichloro(ethylenediamine)platinum(II) in cisplatin-sensitive and resistant human ovarian carcinoma cells. Cancer Res 54:2680-7
McClay, E F; McClay, M E (1994) Tamoxifen: is it useful in the treatment of patients with metastatic melanoma? J Clin Oncol 12:617-26
McClay, E F; Albright, K D; Jones, J A et al. (1993) Tamoxifen modulation of cisplatin cytotoxicity in human malignancies. Int J Cancer 55:1018-22
Mc Clay, E F; Mc Clay, M E; Albright, K D et al. (1993) Tamoxifen modulation of cisplatin resistance in patients with metastatic melanoma. A biologically important observation. Cancer 72:1914-8
McClay, E F; Albright, K D; Jones, J A et al. (1993) Tamoxifen modulation of cisplatin sensitivity in human malignant melanoma cells. Cancer Res 53:1571-6
McClay, E F; Albright, K D; Jones, J A et al. (1992) Modulation of cisplatin resistance in human malignant melanoma cells. Cancer Res 52:6790-6