Effects on mouse uterus of three antitumoral drugs acting upon estrogen and progesterone receptors directly and through other transduction pathways.

Three antitumoral drugs, tamoxifen (Tam), medroxyprogesterone acetate (MPA), and 8-Cl-cyclic AMP (8Cl), were administered separately and in combination to normal adult mice in order to record their effects on uterus weight, on estrous cycle, and on two estrogen receptor (ER) and progesterone receptor (PgR) parameters, namely content and nucleo-cytoplasm distribution. Tam decreased uterus weight (49%) and total ER content (118+/-6 vs 328+/-20 fmol/mg protein in controls) but increased total PgR (1183+/-230 vs 743+/-52 fmol/mg protein in controls) and nuclear retention of ER and PgR. MPA down-regulated PgR content and increased uterus weight (36%), but failed to modify ER and PgR nuclear retention. The only parameter changed by 8Cl was nucleo-cytoplasm PgR distribution. Tam + MPA association produced the same results as Tam alone for ER and PgR nuclear retention, but receptor content was not significantly different from that of controls. Both drugs, administered separately, had opposite effects on PgR content; when both were acting concurrently, an algebraic addition of effects was observed, as if both transcription circuits were triggered independently. Remaining Tam effects, not modified by a combination with MPA, indicated the predominance of Tam on the corresponding parameters. When Tam and 8Cl were administered together, 8Cl counteracted the effect of Tam only on PgR content. When associated with MPA, 8Cl changed the effects of MPA on ER and PgR nuclear retention, whereas on receptor content, only that of ER was increased (502+/-47 vs 328+/-20 fmol/mg protein in controls). These crossed effects indicate that interrelations between different transduction pathways can affect certain functional circuits while sparing others. The possibility of acting pharmacologically upon different transcription pathways represents a novel approach to modify drug effects directed to specific transduction targets through cross-talk between their components.