The interaction between cisplatin (cDDP) and tamoxifen (TAM) was evaluated in the human head and neck squamous-carcinoma cell lines UM-SCC-10B and UM-SCC-5. Synergy between cDDP and TAM was demonstrated in the UM-SCC-10B cell line. Concordant with the synergistic effect between cDDP and TAM, the rate of development of resistance to cDDP was delayed when selections were performed in the presence of TAM. However, in the UM-SCC-5 cell line, TAM was neither synergistic nor did it delay the development of cDDP resistance. The difference with respect to the synergistic interaction of cDDP with TAM and the effect on the development of cDDP resistance in the UM-SCC-10B and UM-SCC-5 cell lines was not related to any significant difference in the accumulation of the cDDP analog [3H]-cis-dichloro(ethylenediamine)platinum(II) (DEP), drug sensitivity [concentrations inhibiting colony formation by 50% (IC50 values) were 6.5 and 7.2 microM for cDDP and 3.5 and 3.2 microM for TAM, respectively], the number of estrogen and progesterone receptors (negative in both cell lines), the number of antiestrogen binding sites (404 +/- 85 and 353 +/- 24 fmol/mg protein, respectively), or the affinity of TAM for these binding sites (1.7 and 1.5 nM, respectively). Importantly, however, we demonstrated that TAM can delay the emergence of resistance to cDDP in head and neck carcinomas and that this effect is linked to the nature of the interaction between cDDP and TAM.