Effects of various synthetic retinoids on proliferation and immunophenotype of human melanoma cells in vitro.
Since response rates in human melanoma are low with currently available therapeutic modalities, we have reevaluated the potential usefulness of retinoids as new alternatives for therapy of metastatic melanoma. Nine synthetic retinoids with high affinity and/or selectivity for the retinoic acid receptors (RAR) alpha, beta, and gamma were studied in comparison to all-trans retinoic acid (RA) for their in vitro effects on melanoma cell proliferation and for their immunomodulating capacities using four human melanoma cell lines. Eight out of ten retinoids tested had no effect on melanoma cell growth, whereas the remaining two compounds with high RAR-gamma selectivity (CD437 and CD2325) showed a dose-dependent antiproliferative effect on all melanoma cell lines with IC50 (concentration inhibiting response by 50%) values between 10(-6) and 10(-7)M. Further analyses showed that paracrine-mediated tumor cell growth inhibition such as induction of transforming growth factor (TGF)-beta described as one mechanism of retinoid action and enzyme systems such as tyrosinase and monoamine oxidase were not involved in mediating the antiproliferative effects exerted by the two retinoids. Four of nine retinoids modulated HLA-DR expression on human melanoma cells, and expression levels of intercellular adhesion molecule 1 (ICAM-1) was increased by another subset of compounds. These effects were, however, not correlated to the receptor selectivity of the retinoids. The potent growth inhibitory effect of the RAR-gamma-selective retinoids and the immunomodulating capacities of the retinoids open an interesting alternative for new antiproliferative and immunomodulatory strategies in the treatment of metastatic melanoma.
Schadendorf
D
D
University Hospital Rudolf Virchow, Department of Dermatology, Free University of Berlin, Germany.
Worm
M
M
Jurgovsky
K
K
Dippel
E
E
Reichert
U
U
Czarnetzki
B M
BM
D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics; D016130:Immunophenotyping; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D008545:Melanoma / Q000276:immunology / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000145:classification / Q000187:drug effects / Q000502:physiology; D012176:Retinoids / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D006684:HLA-DR Antigens; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1