Pharmacokinetic variability induced drug resistance in tumors
The clinical resistance to anticancer agents is recognized as a major problem in cancer therapy. The drug-dependent resistance mechanisms are often associated with ADME (drug absorption, distribution, metabolism, elimination) systems. Besides the pharmacokinetic variability in the systemic circulation of a drug, the intratumoral drug disposition can also contribute to the resistance mechanisms to anticancer agents. Drug resistance is associated with 1) the high variability of extracellular and intracellular drug level ratios, 2) the synergistic interplay between the key systems involved in tumor-specific ADME (drug-metabolizing enzymes, uptake and efflux transporters), 3) the genetic polymorphisms of these components, 4) and the strong genomic instability in cancer subclones that leads to a highly variable expression of these proteins. Most anticancer agents are enzymatically transformed to inactive, active and/or toxic metabolites; therefore, the function of drug-metabolizing enzymes (e.g. cytochrome P450 enzymes) is of high importance in drug resistance. Genetic polymorphisms (loss-of-function or gain-of-function mutations) and genomic instability induced variability (deletion or multiplication) in drug elimination is investigated 1) in parental (sensitive) and resistant cell-lines that overexpress drug-metabolizing enzymes and/or transporters, 2) and in tumor samples from patients. Our aim is to adapt and further develop assays to reveal resistance mechanisms against the anticancer agent paclitaxel (e.g. cytotoxicity testing, assaying CYP mRNA and CYP deletion/multiplication, CYP overexpression in adenocarcinoma cell lines). In parallel, lung adenocacinoma samples are collected at the National Korányi Institute of TBC and Pulmonology. CYP polymorphisms in patients and CYP copy number variations in tumors are determined, and the association with therapeutic outcome is followed.
Katalin Monostory, Gergely Szakács