[Ras signaling pathway as a target for farnesyltransferase inhibitors--a new, promising prospects in the treatment for malignant disorders].
Ras mutation is observed in 20-30% of human malignancies. Ras proteins belong to the family of G-proteins, which are able to bind and hydrolyze guanosine triphosphate reversibly. They are responsible for signal transduction within cell. Ras undergoes several steps of posttranslational modification, but only farmesylation is necessary for its biologic activity. The crucial enzyme of farnesylation - farnesyltransferase (FT-ase) has become a major target for the development of new anticancer agents--farnesyltransferase inhibitors (FTI). Mutation of Ras results in the abrogation of its normal GTP-ase activity and subsequently it causes a permanent activation of Ras with uncontrolled growth and proliferation of cells. Recently published trials revealed, that FTI are highly effective in several malignant disorders, including myeloid leukemias. FTI are bioavailable after oral administration and have an acceptable toxicity profile. No enhanced myelosuppression effect was noted. It was observed, that FTI may increase cytotoxic effect of some antineoplastic drugs and radiotherapy. It seems that these agents are an interesting and promising therapeutic option for patients, who were resistant to conventional chemotherapy. The benefits of ambulatory drug administration may improve the quality of life in oncological patients. The II phase trials with FTI are under way and we hope, that these agents will find an unquestionable position in treatment of patients with malignancies.
Helbig
Grzegorz
G
Katedry i Kliniki Hematologii i Transplantacji Szpiku, Slaskiej Akademii Medycznej w Katowicach. grzegorz.helbig@inetia.pl
Hołowiecki
Jerzy
J
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051231:Farnesyltranstransferase; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000235:genetics; D011905:Genes, ras / Q000187:drug effects* / Q000235:genetics; D006160:Guanosine Triphosphate / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D017354:Point Mutation / Q000187:drug effects / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D051231:Farnesyltranstransferase; D019204:GTP-Binding Proteins; D006160:Guanosine Triphosphate; D007093:Imidazoles; D010880:Piperidines; D011725:Pyridines; D015363:Quinolones; C425231:L 778,123; C115354:lonafarnib; D003986:Dibenzocycloheptenes; C402769:tipifarnib