Approximately 10% of colorectal carcinomas demonstrate microsatellite instability (MSI). Distinct from the majority of colorectal cancers with chromosomal instability (CIN) which harbour allelic imbalance from chromosomal polyploidy and aneuploidy, MSI tumours retain intact chromosomal numbers but contain microsatellite repeats due to deficiency in mismatch repair which are thought to contribute to the early steps of tumourigenesis in colorectal cancer. While emerging clinical data has highlighted improved prognosis of tumours with MSI in early colorectal cancer and potentially circumventing the need for adjuvant chemotherapy, the implications of MSI deficiency in metastatic colorectal cancer (mCRC) remain uncertain. In order to assess the significance of MSI in mCRC, a broad literature review was carried out through online PubMed search on published articles encompassing pathological and clinical papers. This included pathological studies identifying the correlation with MSI status between primary sites and metastases, and chemotherapeutic studies assessing the impact of fluoropyrimidine-, irinotecan- and oxaliplatin-based regimens on mCRC with MSI.
With the progress of research in molecular biology and greater understanding of cell signalling systems emerge an increasing array of potential targets for the therapy of cancer. While traditional chemotherapy aims to elicit tumour cell death, it also produces undesirable side effects on physiologically proliferating cells. By isolating cell surface receptors which link specific intracellular secondary messenger pathways, researchers are increasingly able to define the biological network which drives cellular function. Of importance are routes involved in malignant transformation, proliferation, survival and angiogenesis. Thus targeted therapy is directed to specific differential growth processes particular to malignant tumours. The principle mode of action generally involves the "lock-and-key" mechanism and identifying the "Achilles' heel" for drug action. Various targeted agents have been studied and many have translated into significant clinical benefit. This chapter will describe some examples which illustrate the role of this approach in gastrointestinal cancers.
Pancreatic neuroendocrine tumors are rare and the majority of patients present in the advanced stage. Over the past few decades, treatment for patients with metastatic well- or moderately differentiated pancreatic neuroendocrine tumors have not significantly impeded tumor progression nor improved survival. However, recent mapping of intracellular signaling pathways promoting tumor proliferation, growth, and angiogenesis has presented mammalian target of rapamycin (mTOR) as a potential target within the phosphatidylinositol 3-kinase-Akt pathway. With the development of the new-generation mTOR inhibitor everolimus, a series of clinical trials over the last 5 years have demonstrated significant benefit in delaying tumor progression. This review focuses on the mechanism of mTOR inhibition and traces the development of clinical evidence for the use of mTOR inhibitors in well- to moderately differentiated advanced pancreatic neuroendocrine tumors.
Patupilone given at a dose of 8 mg/m(2) IV over 20 min every 3 weeks was associated with high levels of toxicity and no significant evidence of efficacy in patients with pre-treated colorectal cancer.
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