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Current Cancer Treatment - Novel Beyond Conventional Approaches, 2011

Current Cancer Treatment-Novel Beyond Conventional Approaches 4 parameters guide tumor treatment ... more Current Cancer Treatment-Novel Beyond Conventional Approaches 4 parameters guide tumor treatment decisions, as well as the disease prognosis evaluation (Arnone et al., 2010). It is likely that BC classification may require revision, as a recent cDNA microarray gene expression profiling study has classified BC into 5 distinct subtypes based on variations in gene expression patterns (Haupt, 2010). These 5 subtypes are luminal A and luminal B, normal breastlike, HER2 overexpressing, and basal-like subtypes (Nielsenet al., 2004; Haupt et al., 2010). BC treatment commonly follows combinatory schemes comprising surgery, radiotherapy, chemotherapy, and/or hormonotherapy. Surgical strategies of breast tumors vary according to the extent of the disease, which is evaluated as in situ carcinoma or invasive cancer. Lobular and ductal in situ carcinomas are treated, respectively, with excisional biopsy then prophylactic use of tamoxifen, or another hormonotherapy approach, for five years (depending on the tumor ER status), and mastectomy followed by radiotherapy. Partial mastectomy may also be considered. Although the discussion of BC surgery is beyond the scope of the present work, it is worthwhile to point that the decision to pursue with mastectomy, partial or radical, must consider that its curative benefit overpasses its mutilation impact on women's psychological health (Barros et al., 2009). On the other hand, invasive BC carcinomas are differentially treated depending on the tumor size, free surgical margins and residual post-surgical disease, skin damage, and the existence of metastasis. When BC is diagnosed as a tumor of 3 cm or less with free surgical margins, the recommendation is conservatory surgery, characterized by segmentar resection, followed by radiotherapy (Veronesi et al., 1995). Axillary linfadenectomy dissection is also advised whenever sentinel lymph node (SLN) tests positive for malignancy, as it indicates lymphoid drainage of the primary tumor micrometastasis (Fisher et al., 1997a). Nonetheless, invasive BC carcinomas larger than 3 cm at the disease diagnosis, both mastectomy and linfadenectomy are indicated. Breast reconstitution may be considered for patients presenting good clinical conditions (Barros et al., 2009). Regarding the conventional pharmacologic control of BC, there are several multidrug regimens preconized for neoadjuvant, adjuvant, or palliative chemotherapy approaches. As for any other antineoplastic approach, BC chemotherapy combines drugs with distinct cytotoxic mechanisms of action aiming the avoidance of drug resistant phenotype development by cancer cells. In this context, current BC chemotherapy schemes include drugs classified as anthracyclines, alkaloid taxanes, nitrogen mustard alkylating agents, antimetabolic drugs, and hormonotherapeutic agents. Of interest, the relevant pharmacodynamic aspects of the cited drugs will be briefly addressed [Drugs mechanisms of action have been reviewed by Brunton (2010)]. Anthracyclines, which include doxorubicin and epirrubicin, are considered cytotoxic antibiotics that comprise a tetracycline ring coupled to a quinone or a hydroquinone ring by a daunosamine sugar. They form stable complexes with DNA and the enzyme topoisomarase II, therefore preventing the DNA double strand to be rebuilt, and subsequently inducing cellular apoptosis. Moreover, anthracyclines react with CYP 450 reductase in the presence of NADPH to form semiquinone radicals that, in turn, react with oxygen species. These free radicals can oxydate DNA nitrogen-bases, additionally resulting in cellular death. It is relevant to point that the reactive free radicals are also the cause of major cardiotoxicity, which can be cumulative and irreversible. Another important antineoplastic drug that inhibits topoisomerase II is etoposide. The alkaloid taxane paclitaxel interact with-tubuline within the cytoskeleton microtubules structure, stabilizing the polymer and preventing cellular division, thus inducing cellular www.intechopen.com Breast and Ovarian Cancer Treatment: Facing Forward Women´s Health Care 5 death. It has been also demonstrated that paclitaxel induces apoptosis through the interaction and further inhibition of the anti-apoptotic molecule Bcl-2. Vinorelbine is a synthetic alkaloid that also disrupts microtubule dynamics; therefore, inhibiting cellular division. The ultimate effect is cell cycle arrest; however, major peripheral neurotoxicity is also observed. Although not an alkaloid, a new drug that interferes with microtubule dynamics is the semi-synthetic epothilone B analog, ixabepilone: a 16-membered polyketide macrolide with a chemically modified lactam substitution for the naturally existing lactone that inhibits microtubule. Nitrogen mustards, as cyclophosphamide, are DNA-alkylating drugs. Specifically in the case of cyclophosphamide, the pro-drug is metabolized by CYP2B in the liver to acrolein and phosphoramide mustard. Whereas the former can cause hemorrhagic cystitis, the latter undergoes a series of reactions to ultimately alkylate DNA and disrupt its double strand structure, causing cellular apoptosis. In addition, the compound can cause cardiotoxicity, and hepatic vein occlusive disease. In brief, the bis-chloroethyl-amine undergoes an intramolecular cycling process to form the unstable ethylene-immonium structure that further transforms the tertiary amine into an unstable quaternary amine. Then, the ring opens to form the reactive carbonium ion that reacts majorly with the N7 of guanine within the DNA structure. It has been documented that the 7-alkyl-guanine confers lability to the imidazole ring that opens, inducing DNA depurination through the excision of guanine residues, and cellular death. Moreover, cellular apoptosis seems to be coupled to the tumor suppressor gene p53. Similar mechanism of action has been associated to the platinumbased compounds, as cisplatin and carboplatin. The rational to develop antimetabolic drugs to control cancer progress relied on the idea that cancer cells have higher metabolic rates than the normal counterparts. The first antimetabolic drug to become available was methotrexate, which interacts with the catalytic site of the enzyme dihydrofolate reductase, thus decreasing the amount of tetrahydrofolate, and inhibiting the synthesis of thymidylate, purines, serine, and threonine. The critical event is the interruption of DNA, RNA, and protein synthesis, leading to cellular apoptosis. Similarly to the observation with the DNA-alkylating agents, methotrexate mechanism of action seems to be mediated by p53. Of clinical interest, methotrexate can cause dermatitis, pneumonia, nephrotoxicity, and neurotoxicity. Another antimetabolic drug used to control BC is 5-flourouracil. This is metabolized to 5-fluoro-2'-desoxyuridine 5'-phosphate that forms a stable ternary complex with the enzyme thymidylate synthetase; so, preventing RNA synthesis, and leading to cellular death. In addition, the drug can be converted in 5fluorouridine, which incorporates into the RNA molecule, altering its processing and function, hence resulting in cellular apoptosis. Other important antimetabolic drugs are capecitabine, which is metabolized to 5-fluorouracil, and gemcitabine. The latter is metabolized to difluorodeoxycitidine diphosphate that inhibits ribonucleotide reductase, then preventing DNA synthesis, and difluorodeoxycitidine triphosphate, which is incorporated into DNA leading to precocious termination of the nascent molecule and cellular death. Lastly, the well-established role of estrogen in tumorigenesis has corroborated with the use of modulators of the hormone interaction with its specific receptors or of its biosynthesis. The so called hormonotherapy consists on the use of ER antagonists, as tamoxifen, raloxifen, and lasofoxifen or aromatase inhibitors. Whereas the former class of drugs inhibits the estrogen-induced transcription of growth-regulating factors, as IGF-1, the latter blocking the conversion of adrenal androgens to estrogens by the enzyme CYP19 aromatase (Sikora et al.,