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Free Content Editorial [Hot Topic: Targeted Cancer Therapies: Current Status and Future Directions (Guest Editors: Ioannis Starakis)]

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During the last three decades, the advances in medical technology have elucidated many of the aspects of genetic and epigenetic pathways that commence the evolution of neoplasia. Standard therapeutic interventions include local control (surgery and/or radiotherapy) along with a combination of chemotherapeutic regimens for a systemic approach. Nevertheless, the appearance of genetically determined resistance to chemotherapeutic agents leads to treatment failures. Targeted tumor therapies consist of molecularly targeted substances that hamper the development and dissemination of malignant cells by interfering with the molecules implicated in cancer expansion and spreading. Targeted treatments, by focusing on specific molecular and cellular modifications of cancer cells, may be more successful than standard chemotherapy and, more importantly, less harmful to normal cells. There have already been some successful attempts of specialized targeting of malignant cells such as the antihormonal manipulation of testosterone and estrogen receptors in prostate and breast cancer, respectively. Our aim is to comprehensively review the current status and future directions of targeted cancer treatments focusing on colorectal cancer, the development of histone deacetylase inhibitors, the implication of endo-cannabinoid system in cancer therapies, the benefits from targeted treatment in lung adenocarcinoma patients, the incorporation of these agents in advanced gastric carcinoma, the emerging therapeutic targeted interventions in tumor-induced bone disease, the effect of targeted therapy in advanced renal cell carcinoma, and, finally, the resistance pathways to epidermal growth factor receptor tyrosine kinase inhibitors, in sufferers from non-small cell lung carcinoma.

For decades before the year 2000, leucovorin (LV)-modulated 5-fluorouracil (5-FU) was the only active agent against colorectal cancer, but since then oxaliplatin and irinotecan and also three humanized monoclonal antibodies have been added in our armamentarium against this disease. These antibodies are targeting the vascular endothelial growth factor (bevacizumab) and the epidermal growth factor receptor (panitumumab and cetuximab). The purpose of adjuvant chemotherapy in colon cancer patients after a potentially therapeutic surgical resection is to eliminate micro-metastases, diminish recurrence and also augment cure rates. Adjuvant chemotherapy seems to be more beneficial in stage III (node-positive) disease, while advantage in stage II disease remains ambiguous and most authorities agree that bevacizumab and cetuximab are not recommended in this setting. On the other hand, in patients with non-operable, metastatic colorectal cancer the addition of bevacizumab to an assortment of first-line regimens have showed that improves outcomes. Nonetheless, this favourable response is accompanied by serious adverse events such as thromboembolic incidents, bleeding diathesis, bowel perforation, nephritic syndrome and hypertension. The second-line use of bevacizumab with another chemotherapeutic combination in patients who have failed to respond to the first-line bevacizumab containing regimens is still not established due to lack of sufficient evidence and more randomized clinical trials are needed. It could only be regarded as an option in a special patient group with K-ras mutations, because in those patients the administration of anti- epidermal growth factor receptor (EGFR) regimens is contraindicated.

The combination of the anti-EGFR agent, cetuximab with irinotecan is valuable for patients with wild type K-ras tumors who do not respond to irinotecan and also as monotherapy for those who can not tolerate an irinotecan-based combination.

Panitumumab has been used as monotherapy for patients with metastatic wild-type K-ras colorectal cancer, when all other agents have failed. The precise role of panitumumab in combination with chemotherapy, particularly for first-line therapy of metastatic colorectal cancer has to be further investigated.

There is also accumulative evidence that in patients with wild type K-ras tumors, the combination of first and second line panitumumab with irinotecan or oxaliplatin regimens is more effective than chemotherapy alone but toxicity with severe diarrhoea and electrolytic disturbances was prominent. Further clinical trials comparing cetuximab versus panitumumab, but also each drug versus a bevacizumabcontaining combination are imperative.

A deviant histone deacetylases activity has been recognized in several tumor types, rendering them an attractive potential therapeutic target.........
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Document Type: Research Article

Publication date: 2011-04-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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