Tamoxifen-induced drug resistance

Finally, therapeutic sequencing of different hormonal agents is fast becoming a common clinical practice, and fulvestrant is a good treatment choice to extend the opportunity for using endocrine therapies before reliance upon cytotoxic chemotherapy is necessary. Further research is required in order to evaluate the optimal sequence, both in clinical practice as well as in the laboratory, to choose the correct treatment of breast cancer in each person after the appearance of tamoxifen-induced drug resistance (Robertson 2004 Osipo et al. 2004 Johnston 2004 Robertson et al. 2005). 

Obesity can cause insulin resistance and hepatic steatosis, which can lead to nonalcoholic steatohepatitis (NASH) in some patients (Pessayre and Fromenty 2005). Patients with NASH have an impaired ability to resynthesize ATP after a fructose challenge (Cortez-Pinto et al. 1999). Their hepatic mitochondria exhibit ultrastructural lesions with paracristaUine inclusions in megamitochondria (Caldwell et al. 1999 Sanyal et al. 2001). Patients with NASH have decreased protein expression of several mtDNA-encoded polypeptides and lower activity of respiratory complexes (Perez-Carreras et al. 2003). Thus, obesity-associated NASH combined with the administration of drugs impairing mitochondrial (3-oxidation may additively damage mitochondria to aggravate steatosis and steatohepatitis. Indeed, obesity has been shown to increase the risk of tamoxifen-induced steatosis and steatohepatitis in women (Bruno et al. 2005). 

Miproxifene (TAT-59) is a prodrug of 4-hydroxy-tamoxifen that has been developed for tamoxifen-resistant carcinoma, but relatively little information has been published on this drug. Compared with tamoxifen, miproxifene inhibits estradiol-stimulated proliferation of MCF-7 cells at a threefold lower dose than that of tamoxifen, and of dimethyl-benzanthracene (DMBA)-induced rat mammary tumors at a dose tenfold lower than tamoxifen (Toko et al. 1990). In any event, in preclinical castrated rat models, it shows an endometrial stimulation activity that is similar to that of tamoxifen, which means it has limited potential use in the prevention or treatment of osteoporosis or cardiovascular disease (Shibata et al. 2000). Similarly, considering the preclinical findings of endometrial stimulation reported on GW5638 (Willson et al. 1997), it is likely that this new SERM belonging to the triphenylethylene family will be limited in clinical use to the treatment of advanced tamoxifen-resistant breast cancer once its efficacy is demonstrated in human clinical trials. 

---