Future oncology
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Standard whole-breast irradiation consisting of a dose of 45-50 Gy over 5 weeks with or without the addition of a boost to the tumor bed has equivalent survival to mastectomy and is considered to be the standard of care for most patients with early-stage breast cancer. Newer techniques have been developed to shorten the course of radiation or limit normal tissue exposure in an attempt to increase accessibility to and tolerance of radiation therapy. This article will review some of the newer regimens and techniques for treating early-stage breast cancer after breast-conserving surgery.
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Review
Ridaforolimus: a promising drug in the treatment of soft-tissue sarcoma and other malignancies.
Ridaforolimus (deforolimus; AP23573; MK-8669) is a novel sirolimus derivative manufactured by ARIAD Pharmaceuticals and acquired by Merck. It is a small-molecule kinase inhibitor of the mTOR in clinical development for the treatment of cancer. Both intravenous and oral formulations of the agent are being tested in cancer clinical trials. ⋯ With single-agent ridaforolimus, mucositis and myelosuppression were dose-limiting toxicities. In advanced soft-tissue sarcoma, single-agent ridaforolimus was associated with a 29% clinical benefit rate and 2% partial response rate. A Phase III trial has recently been reported to have met its primary end point.
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Anthracycline-based regimens became the standard of care for early breast cancer patients based on the survival advantage they provide over nonanthracycline-containing regimens. The addition of taxanes, and subsequently trastuzumab in HER2-overexpressing patients, to anthracyclines further improved their efficacy in several studies involving high-risk early breast cancer patients. Concern over toxicity initially surfaced after anthracyclines were reported to carry an increased risk of cardiotoxicity and secondary leukemia. ⋯ This has led to the development of regimens featuring a taxane without an anthracycline; these protocols vary in design and have different toxicity and efficacy profiles. Ongoing investigations are centered on the optimization of nonanthracycline regimens, prospective exploration of molecular markers to identify populations of patients who will derive maximal benefit from anthracycline-based chemotherapy, and the identification of less cardiotoxic formulations of existing anthracycline agents. Perhaps most importantly, a rapidly growing understanding of the biological heterogeneity of breast cancer is likely to lead to an individualized standard of care guided by particular patient and tumor characteristics.
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Sphingolipids have emerged as bioeffector molecules, controlling various aspects of cell growth and proliferation in cancer, which is becoming the deadliest disease in the world. These lipid molecules have also been implicated in the mechanism of action of cancer chemotherapeutics. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative responses, such as cell growth inhibition, apoptosis induction, senescence modulation, endoplasmic reticulum stress responses and/or autophagy. ⋯ In addition, ceramide metabolism to generate sphingosine-1-phosphate (S1P) by sphingosine kinases 1 and 2 mediates, with or without the involvement of G-protein-coupled S1P receptor signaling, prosurvival, angiogenesis, metastasis and/or resistance to drug-induced apoptosis. Importantly, recent findings regarding the mechanisms by which sphingolipid metabolism and signaling regulate tumor growth and progression, such as identifying direct intracellular protein targets of sphingolipids, have been key for the development of new chemotherapeutic strategies. Thus, in this article, we will present conclusions of recent studies that describe opposing roles of de novo-generated ceramides by ceramide synthases and/or S1P in the regulation of cancer pathogenesis, as well as the development of sphingolipid-based cancer therapeutics and drug resistance.
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The combination of radiotherapy with chemotherapeutic agents that sensitize tumor cells to ionizing radiation has long been regarded as a promising strategy to enhance cancer therapy. Many chemotherapeutic agents interact with radiation and enhance the cytotoxic or anti-tumor effect of radiation through a number of mechanisms. These include an increase in initial radiation damage, inhibition of cellular repair, cell cycle redistribution, enhancement of apoptosis, counteracting hypoxia and overcoming accelerated repopulation. This article focuses on the role of cell cycle perturbations in the radiosensitivity of cancer cells.