UGT1A1*28 and other UGT1A polymorphisms as determinants of irinotecan toxicity.

Irinotecan is a drug commonly used for the treatment of cancer patients, both as a single agent or in combination therapy. Neutropenia and diarrhea are the dose-limiting toxicities. Genetic variations of proteins involved in irinotecan metabolism and transport have been considered in the development of irinotecan toxicity. In particular, polymorphisms affecting UDP-glucuronosyltransferase isoform 1A1 (UGT1A1) expression or activity are being investigated. Among these, UGT1A1*28 has been considered as the major predictive pharmacogenetic marker for severe hematological toxicity (neutropenia). However, translation to clinical practice of UGT1A1*28 testing as a predictive marker of adverse effects needs to be further investigated and the available data are not conclusive in defining a precise genotype-based dosage. Further prospective studies are required to reach a personalization of chemotherapy with irinotecan.

Pharmacology of epidermal growth factor inhibitors.

Research into the molecular bases of malignant diseases has yielded the development of many novel agents with potential antitumor activity. Evidence for a causative role for the epidermal growth factor receptor (EGFR), which is now regarded as an excellent target for cancer chemotherapy in human cancer, leads to the development of EGFR inhibitors. Two classes of anti-EGFR agents are currently in clinical use: monoclonal antibodies directed at the extracellular domain of the receptor, and the low-molecular-weight receptor tyrosine kinase inhibitors acting intracellularly by competing with adenosine triphosphate for binding to the tyrosine kinase portion of the EGFR. The effect on the receptor interferes with key biological functions including cell cycle arrest, potentiation of apoptosis, inhibition of angiogenesis and cell invasion and metastasis. Cetuximab, a monoclonal antibody, and the receptor tyrosine kinase inhibitors gefitinib and erlotinib are currently approved for the treatment of patients with cancer. New agents with clinical activity are entering the clinic, and new combinatorial approaches are being explored with the aim of improving the potency and pharmacokinetics of EGFR inhibition, to increase the synergistic activity in combination with chemotherapy and overcome resistance to the EGFR inhibitors.

Pharmacology of epidermal growth factor inhibitors.

Research into the molecular bases of malignant diseases has yielded the development of many novel agents with potential antitumor activity. Evidence for a causative role for the epidermal growth factor receptor (EGFR), which is now regarded as an excellent target for cancer chemotherapy in human cancer, leads to the development of EGFR inhibitors. Two classes of anti-EGFR agents are currently in clinical use: monoclonal antibodies directed at the extracellular domain of the receptor, and the low-molecular-weight receptor tyrosine kinase inhibitors acting intracellularly by competing with adenosine triphosphate for binding to the tyrosine kinase portion of the EGFR. The effect on the receptor interferes with key biological functions including cell cycle arrest, potentiation of apoptosis, inhibition of angiogenesis and cell invasion and metastasis. Cetuximab, a monoclonal antibody, and the receptor tyrosine kinase inhibitors gefitinib and erlotinib are currently approved for the treatment of patients with cancer. New agents with clinical activity are entering the clinic, and new combinatorial approaches are being explored with the aim of improving the potency and pharmacokinetics of EGFR inhibition, to increase the synergistic activity in combination with chemotherapy and overcome resistance to the EGFR inhibitors.