Breast cancers, drug-resistant

Weinberg OK, Marquez-Garban DC, Pietras RJ. New approaches to reverse resistance to hormonal therapy in human breast cancer. Drug Resist Update. 2005 8 219-233. 

The in vitro system has some limitations and it can be used only as a model to address acquired drug resistance, because cell lines may not accurately reflect the in vivo situation of patients treated with anticancer drugs. In vivo analysis using patient samples to study anti-cancer drug resistance are described in the published literature. Chang and coworkers (64) showed that the gene-expression patterns from mRNA derived from needle biopsies of breast cancer patients treated with the anticancer drug, docetaxel, could be predictive of response to the therapy. 

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

Mao Q and Unadkat JD. Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J 2005 7 E118-33. 

Breast Cancer Resistance Protein (BCRP, also known as MXR or ABCP), first cloned from mitoxantrone and anthracycline-resistant breast and colon cancer cells [188, 189] is a half-transporter efflux pump believed to function as a homo-or hetero-dimer. Following its identification, BCRP-mediated drug resistance was observed for topoisomerase inhibitors including camptothecins [190, 191] and in-dolocarbazoles [192]. In normal tissues, BCRP was detected in placental syncytio-trophoblasts, hepatocyte canalicular membrane, apical intestinal epithelia and vascular endothelial cells [193]. These findings support the important role BCRP plays in modulating topotecan bioavailability, fetal exposure and hepatic elimination [194]. Considering that the substrates and tissue distributions for BCRP overlap somewhat with MDR1 and MRPs [195], additional studies will be required to define the relative contribution of each of these transporters in the overall and tis-... 

The high frequency of the C allele in the African group may also contribute to the high incidence of drug resistance and the prevalence of more aggressive tumors, in diseases such as breast cancer, in individuals of African origin [66]. 

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

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. 

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). 

L. Zampieri, P. Bianchi, P. Ruff, and P. Arbuthnot. Differential modulation by estradiol of P-glycoprotein drug resistance protein expression in cultured MCF7 and T47D breast cancer cells. Anticancer Res. 22 2253-2259 (2002). 

K. Shiozawa, M. Oka, H. Soda, M. Yoshikawa, Y. Ikegami, J. Tsurutani, K. Nakatomi, Y. Nakamura, S. Doi, T. Kitazaki, Y. Mizuta, K. Murase, H. Yoshida, D.D. Ross, and S. Kohno. Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, a coumermycin antibiotic. Int J Cancer. 108 146-151 (2003). 

P. Pavek, G. Merino, E. Wagenaar, E. Bolscher, M. Novotna, J.W. Jonker, and A.H. Schinkel. Human breast cancer resistance protein Interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-l-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine. J Pharmacol Exp Ther. 312 144—152... 

Gene amplification 1 Many oncogenes are present in multiple copies erbB amplified in certain breast cancers Dihydrofolate reductase genes are amplified in some tumors, leading to drug resistance... 

Lavie, Y., Harel-Orbital, T., Gaffield, W. and Liscovitch, M. (2001). Inhibitory effect of steroidal alkaloids on drug transport and multidrug resistance in human breast cancer cells. Anticancer Res., 21, 1189-1194. 

Imai, Y., Nakane, M., Kage, K., et al. (2002) C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q14IK protein and low-level drug... 

---