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Endocrine therapies have been used for more than a century to treat breast cancer. A huge body of evidence from preclinical and clinical studies substantiates the outstanding role of estrogens in initiation and in promotion of almost two-thirds of breast cancer [1, 2]. Since the initial observations of Beatson who, in 1896 reported of dramatic tumor responses after bilateral oophorectomy in premenopausal women with advanced breast cancer, the suppression of the estrogen activity has represented the rationale for the manipulations aimed to affect the growth of breast cancer [3, 4]. Initially, surgical procedures as oophorectomy and adrenalectomy were shown to induce some tumor regression; since then, the development of drugs which negatively affect the production and/or the activity of estrogens led to a widespread use of hormonal manipulations [4]. [ABSTRACT FROM AUTHOR]

As a result of significant advances in fundamental research over the past 20 years, the process of signal transduction pathways involving receptor tyrosine kinases is now recognised to play a key role in the regulation of several physiological processes such as cell cycle,metabolism, growth, differentiation and proliferation. In addition, and more recently acknowledged, abnormal activation of these signal transduction pathways may lead to increased and uncontrolled cellular proliferation and a decrease in apoptosis, thus playing an important role in the development and growth of many human epithelial tumours. [ABSTRACT FROM AUTHOR]

Angiogenesis, the formation of new blood vessels from the existing vasculature, is a physiological process in wound healing and the menstrual cycle, but has a pathological role in several diseases, such as retinopathy, rheumatoid arthritis and cancer. One of the hallmarks of cancer is the presence of sustained angiogenesis after tumors have made the angiogenic switch [1, 21]. Angiogenesis is a multi-step process in which endothelial cells have to become activated, subsequently proliferate and migrate in the direction of the angiogenic stimulus, which will only be possible after breakdown and remodeling of the extracellular matrix (ECM) so that tube formation can take place. Finally, the newly formed blood vessel has to be stabilized by pericytes and fibroblasts. This complicated and highly orchestrated process is regulated by multiple factors, such as growth factors, proteases (matrix metalloproteases) and integrins. Important driving forces in tumor-induced angiogenesis are hypoxia and oncogenes [3-6]. Hypoxia induces via hypoxia inducible factor 1α (HIF-1α) the expression of several angiogenic growth factors, whereas mutated and/or activated oncogenes are also capable of inducing the upregulation of angiogenesis stimulating factors and/or the downregulation of angiogenesis inhibiting genes and proteins. [ABSTRACT FROM AUTHOR]

In general medicine, oral ingestion is the most common way of drug administration, being convenient, safe and effective for most agents. In contrast, in oncology most anticancer agents are delivered by intravenous (iv) injection. This is probably due to the narrow therapeutic index of many antineoplastic drugs and the pharmacologic observation that oral administration often results in a large intra-and intersubject variability in drug exposure. However, the burden of iv administration is evident: every iv injection carries, although small, a risk of bleeding, extravasation, infection and thrombosis and requires medically qualified personnel at a hospital setting. Moreover, especially in cancer patients, repeated iv injections are hampered by the fact that a patient's accessible vein may disappear during chemotherapy due to flebitis or thrombosis. [ABSTRACT FROM AUTHOR]

Over the last two decades there has been a great deal of interest in specific immunotherapies. Particularly in the field of passive immunotherapy, using tumor-specific antibodies, some interesting successes have been reported. The humanized monoclonal antibody, Herceptin, directed to the Her-2-neu antigen is now an established standard modality in the treatment of breast cancer patients, whose tumor is overexpressing the Her-2-neu antigen [1]. Cetuximab, a monoclonal antibody specific for another epidermal growth factor receptor, is about to be registered for the treatment of metastatic colon cancer [2]. The treatment with anti-CD20 monoclonal antibodies improves the prognosis of lymphoma patients and is now considered as a standard immunotherapy for B cell lymphomas [3]. All together it took more than 30 years before monoclonal antibodies have evolved to a standard treatment in cancer. It is important to realize that it was no more than 10 years ago that the perspectives of this type of passive immunotherapy were not so promising. The humanization of monoclonal antibodies was a real breakthrough and opened the way for this type of treatment. [ABSTRACT FROM AUTHOR]

Microtubules are important structural elements in all eukaryotic cells, and essential for mitosis, intracellular transport, and maintenance of cell shape, cellular motility and attachment. They play a key role in modulating interactions with cell-surface receptors and the transmembrane signals generated by these interactions. Microtubules are formed through polymerisation of two different proteins, α -and β-tubulin, under the influence of co-factors such as guanosine triphosphate (GTP)and microtubule associated proteins (MAPs) [1]. [ABSTRACT FROM AUTHOR]

The anthracyclines are derivatives of rhodomycin B, a red-pigmented polyketide antibiotic, isolated in the 1950s from Gram-positive Streptomyces present in an Indian soil sample. Many microorganisms produce and secrete complex antibacterial and antifungal compounds into their surroundings to protect their life-sphere against potential invaders. After the discovery of the antitumor activity and chemistry of rhodomycin B, Farmitalia initiated a program to find new anticancer compounds produced by novel strains of microbes isolated from soil. In 1957, a colony of Streptomyces producing a red pigment was grown from a soil sample taken at Castel del Monte near the city of Andria in southeastern Italy. This microbe produced a substance named daunorubicin after a pre-Roman tribe in southeastern Italy; Di Marco demonstrated antitumor activity in 1963. At nearly the same time this compound was isolated by French researchers at Rhône Poulenc, who named it rubidomycin. Later on, it became clear that rubidomycin and daunomycin were identical and daunorubicin became the only name for this compound. In 1969, Arcamone and his co-workers succeeded in isolating and purifying doxorubicin (14-hydroxydaunomycin) from Streptomyces peucetius variety caesius, a mutant of the original Streptomyces strain found near the Adriatic Sea. [ABSTRACT FROM AUTHOR]

DNA topoisomerase inhibitors, known for their broad antitumour activity, represent one of the most widely used groups of anticancer agents. In spite of the early discovery and long-standing clinical use, the mechanism of action of these agents was not recognized until the 1980s [1-3]. Currently agents available for clinical use include the topoisomerase I inhibitors of the camptothecin class (topotecan and irinotecan) and the topoisomerase II inhibitors in the class of epipodophyllotoxins (etoposide and teniposide). Many new formulations and structurally-related agents are currently undergoing clinical development. This chapter highlights the most important aspects of the past, current and future development of topoisomerase I and II inhibitors, and provides an overview of pharmacology and clinical data, with a focus on recent developments. [ABSTRACT FROM AUTHOR]

The synthesis of DNA requires reduced folates. Purine synthesis requires 10-formyltetrahydrofolate (CHO-FH4 )as a methyl donor and 5,10-methylenete-trahydrofolate (CH2-FH4) as carbon donor in the synthesis of thymidine (Fig.1). Methotrexate inhibits dihydrofolate reductase (DHFR)depleting cells of reduced folates, including CHO-FH4 and CH2 -FH4 [1]. Reduced folate depletion does not account for all inhibition of DNA synthesis seen with methotrexate. Methotrexate is metabolized to methotrexate polyglutamates that contribute to cytotoxicity by directly inhibiting the folate dependent enzymes of thymidylate and purine biosynthesis TS, AICAR, GAR; [ABSTRACT FROM AUTHOR]