Resistance of the Haemopoietic Tumour Cells to the Cytotoxic Drugs. Part II.

Overview

Resistance to cytotoxic drugs is a serious drawback in the treatment of patients with tumours, both of thehaemopoietic and non-haemopoietic origin. The cytotoxic effect of drugs on the malignant cells manifests as theprocess of apoptosis. In the resistant malignant cells, apoptosis becomes prevented by several mechanisms. Themultidrug resistance (MDR) is one of the principal mechanisms when the cancer cells develop resistance to multiplechemically and functionally unrelated cytotoxic compounds. The decrease of the cytotoxic drug concentration at themolecular target site may come from activation of some efflux membrane systems participating in the transport ofcytotoxic drugs out of the cell (e.g. Pgp, MDR, and LRP). Another mechanism of resistance is the increased enzymaticdetoxification of the drug by glutathion-s-transferase system. Changes in the molecular target of the cytotoxic drugsuch as topoisomerase molecule can be also responsible for the resistance. At least two additional mechanisms ofresistance of tumour cells were identified. Resistance can come from either deregulation of proapoptotic mechanismsin tumour cells or by increased activity of reparation processes which control the damaged molecule of DNA. Severalmethods that detect the cause of resistance in distinct cell populations have been developed. The great effort is nowfocused on both the detection of mechanisms of the resistance and on the clinical procedures of overcoming theresistance to cytotoxic drugs.

Key words:
multidrug resistance, apoptosis, efflux systems, topoisomerase, cell cycle, DNA reparation, flow