Cancer Chemotherapy and Drug Metabolism

Abstract

Chemotherapy involving the use of cytotoxic antineoplastic agents remains an important strategy in the overall management of patients with malignant tumors. As with most therapeutic agents, drug-metabolizing enzymes and drug transporters play key roles in determining the pharmacokinetics and overall disposition of antineoplastic agents in the body. In addition, metabolism and transport can be important contributors to 1) the toxicity produced by antineoplastic agents in normal host tissues and 2) the delicate balance between drug sensitivity and resistance displayed by target tumor cells.Several features of antineoplastic drugs make the metabolism of these agents particularly significant. Many antineoplastics display steep dose-response curves and low therapeutic indices, and the toxicities that they produce can be severe and life-threatening. Since cancer chemotherapy often involves the use of multiple antineoplastic agents and supportive drugs in combination regimens, drug interactions represent a real clinical concern (Kivisto et al., 1995). Of particular importance are pharmacokinetic drug interactions that result in clinically significant alterations in host toxicity or therapeutic response. Pharmacokinetic drug interactions in cancer chemotherapy often go unrecognized because toxic reactions to these drugs are common and unpredictable, individual

Glutathione S-transferase P1 and DNA Polymorphisms with the Response to Chemotherapy and the Prognosis of Bone Tumor

“…Our results showed a significant relationship with response to chemotherapy among individuals with GSTP1 Val/Val and ERCC2 A/A genotypes. Results of various subsequent studies have shown that consistent of nature of this relationship (Riddick et al, 2005). A similar association is found in of 2.19(1.15-6.21).…”

Cytochrome P450 pharmacogenetics and cancer

“…P450s expressed at higher levels in the tumour cells than in the surrounding normal tissue offer therapeutic options by the activation of prodrugs specifically in the cancer cells and avoiding undesirable systemic effects (see Riddick et al, 2005). In this respect, there are therapeutic options and opportunities arising from both the enhanced endogenous expression of CYP in tumours and CYP-mediated gene therapy.…”

Chemotherapy and Mechanisms of Resistance in Breast Cancer

“…The first evidence of their involvement in resistance to drugs used in chemotherapy have emerged from research published by scientific groups Schisswelbauer et al (1990), Tew (1994) and Hayes, Pulford, (1995). However, the relationship between GSTs and resistance to chemotherapy remains inconsistent (Riddick et al, 2005). This mechanism of resistance is related to the ability to regulate the action of enzymes involved in catalyzing electrophilic compounds harmful to cells from activation by cytochrome P-450 1A1 and 1B1 (Phase I).…”

“…We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular www.intechopen.com pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure.…”