The new
antiestrogen Droloxifene has a 10-60-fold higher binding affinity to the
estrogen receptor (ER) compared to the related compound
Tamoxifen. A similar relationship was found in growth inhibition studies which showed that
Droloxifene inhibited the different ER positive human
breast cancer cells more effectively than
Tamoxifen, predominantly in
drug concentrations which are found in humans during
therapy. As another consequence of the high stability of the complex formed by
Droloxifene binding to the ER, intermittent exposures with clinically relevant concentrations of
Droloxifene brought about effective growth inhibition of human ER positive
tumor cells even after short-term application.
Droloxifene was found, like
Tamoxifen, to block human
breast cancer cells in G1-phase of the cell cycle. Moreover, cell-cycle data confirmed the superior growth-inhibiting potency of
Droloxifene compared to
Tamoxifen.
Droloxifene was also found to effectively induce expression of the negative
growth factor TGF-beta, to inhibit
IGF-I stimulated cell growth and to prevent
estrogen-stimulated proto-oncogene c-myc expression. Unlike
Tamoxifen,
Droloxifene is a potent inhibitor of protein biosynthesis in ER-positive
breast cancer cells at physiologically relevant concentrations. Lower estrogenic and higher antiestrogenic effects on immature rat uterus indicate a higher therapeutic index for
Droloxifene compared to
Tamoxifen. In vivo,
Droloxifene displayed increased growth inhibition of different
tumors of animal (R3230AC and 13762) and human origin (T61). Furthermore, it was found that the two structurally similar drugs differ in their toxicologic characteristics in the following important respects:
Droloxifene is devoid of any in vivo or in vitro carcinogenic or mutagenic effects, whereas
Tamoxifen causes liver
tumors in rats, induces
DNA adduct formation in rats and hamsters and shows transforming activity in SHE-cells (Syrian hamster embryo fibroblasts). Considerably less toxicity and a lower level of intrinsic estrogenicity was observed even after maximum long-term exposure of different animal species to
Droloxifene, in comparison with
Tamoxifen. Therefore, it can be assumed that
Droloxifene may represent an important step forward in the treatment of mammary
carcinomas in women through its better tolerability and increased efficacy compared with
Tamoxifen. For long-term adjuvant or preventive treatment of
breast cancer,
Droloxifene may well be the safer choice.