[Tamoxifen increases cytotoxic effects of fotemustine. Experimental results on cell lines of human melanoma].
Fotemustine (Fote) is a new aminoacid linked chloroethyl nitrosourea which has been shown to be useful in disseminated malignant melanoma. The aim of the present study was to analyze the cytotoxic effects resulting from the combination of antiestrogens and Fote on human melanoma cell lines. The antiestrogens tested were tamoxifen (TMX 5.10(-7) M and 5.10(-6) M) and 40H TMX (5.10(-8) M and 5.10(-7) M). As a preliminary step, a series of nine human melanoma cell lines was screened in order to identify and quantify the presence of estradiol receptors (ER) in these cell lines. This led to selecting an ER positive (+) cell line. The drugs alone or in combination were then tested against CAL 1 ER (+) and CAL 7 ER (-) melanoma cell lines. Different sequences of drug combinations were tested using clinically compatible drug concentrations. For CAL 1 cells there was a growth inhibitory effect induced by the antiestrogens given alone. Overall, the presence of the antiestrogens resulted in higher cytotoxic effects than when cells were exposed to Fote alone. The lowest IC50 Fote values as compared to Fote alone were generated by the sequences with the antiestrogens administered before Fote. Significantly, these associations with antiestrogens enabled the IC50 values of Fote to be reduced up to 80%. Globally TMX and 40H TMX had similar synergistic effects. TMX and 40H TMX had a modest influence on Fote cytotoxic effects against CAL 7 ER (-) cells. These data may be useful for optimal planning of future clinical trials for malignant melanoma using antiestrogens and nitrosoureas.
Fischel
J L
JL
Centre Antoine-Lacassagne, Nice, France.
Barbé
V
V
Berlion
M
M
Formento
P
P
Berrile
J
J
Bizzari
J P
JP
Milano
G
G
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D008545:Melanoma / Q000737:chemistry / Q000188:drug therapy*; D009607:Nitrosourea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D009943:Organophosphorus Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000032:analysis; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D011960:Receptors, Estrogen; D013629:Tamoxifen; C054368:fotemustine
Le tamoxifène augmente les effets cytotoxiques de la fotémustine. Résultats expérimentaux sur lignées de mélanomes humains.