Multifactorial nature of tumor drug resistance.

Tumor drug resistance (TDR) remains a major obstacle for successful treatment of cancer. Till ninetieth years of past century, resistance of tumors to anticancer drugs was most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism or export of drugs from single cells. Meanwhile it became apparent that TDR was formed at the different level of tumor biological structure: in addition to intracellular mechanisms, interactions of cancer cells (multicellular mechanisms) as well as solid tumor microenvironment (including tumor vascularization, components of extracellular matrix and connective tissue) played an important role in protecting cancer cells from initial drug exposure. The limited ability of cancer drugs to penetrate tumor tissue and to reach tumor cells in a potentially lethal concentration makes a significant contribution to low efficacy of cancer therapy and is often resumed as an occurrence of TDR. Failure to recognize such clinical drug resistance cannot be explained entirely by mechanisms operative at the level of the single cell may lead to disappointing results in clinical trials. Presented data demonstrate a multifactorial nature of TDR. Pharmacokinetics and pharmacodynamics aspects of TDR mechanisms are analyzed. The methods to overcome TDR and to increase the efficacy of cancer therapy are discussed.