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Biological agents and gemcitabine in the treatment of breast cancer.

Advances in molecular biology have facilitated the identification of specific molecular abnormalities and dysfunctions in regulatory pathways in breast cancer cells that not only predict prognosis and therapeutic response but may also function as potential therapeutic targets. The rapidly growing introduction of new molecularly targeted drugs in oncology makes increasingly important to understand the effects of drugs molecular interactions. Gemcitabine (GEM), an analog of cytosine arabinoside, has an established efficacy as single agent as well as in combination in the treatment of breast cancer. GEM is a pyrimidine antimetabolite that is metabolized to difluorodeoxycytidine diphosphate (dFdCDP) and difluorodeoxycytidine triphosphate (dFdCTP). Incorporation of these nucleotides into DNA results in chain termination. dFdCTP is not readily excised by DNA exonuclease, resulting in intracellular accumulation. In addition, gemcitabine inhibits ribonucleotide reductase (RR) an enzyme that produces deoxynucleotides required for DNA synthesis. RR consists of two subunits M1 and M2, which contains the non-heme iron, necessary for the reduction reaction. Nucleoside analogues like GEM and fludarabine inhibit the M1 subunit. Several phase II studies have confirmed the activity of single-agent gemcitabine in the treatment of metastatic breast cancer. Objective response rates range from 14% to 46%, depending on the extent of previous treatment. Hematological toxicity is usually mild, with grade 4 neutropenia generally limited to < 10% of treated patients [1, 2]. The promise of therapies targeted to specific molecular abnormalities in breast cancer is currently confronted by the low than expected efficacy of the agents introduced into clinical practice One area of great interest is how to translate into human trials the synergy of these agents with chemotherapy observed in preclinical models. gemcitabine and EGFR-Tyrosine kinase inhibitors