Guanidino-containing drugs in cancer chemotherapy: biochemical and clinical pharmacology

The pharmacology and clinical application of three guanidino-containing com pounds are reviewed in this commentary with special focus on a new member o f this group of drugs. CHS 828 [N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N " - 4-pyridylguanidine]. m-Iodobenzylguanidine (MIBG) and methylglyoxal bis(gua nylhydrazone) (MGBG) have been extensively studied, preclinically as well a s clinically. and have established use as anticancer agents. MIBG has struc tural similarities to the neurotransmitter, norepinephrine, and MGBG is a s tructural analog of the natural polyamine spermidine. CHS 828 is a pyridyl cyanoguanidine newly recognized as having cytotoxic effects when screening antihypertensive compounds. Apart from having the guanidino groups in commo n, there are many differences between these drugs in both structure and the ir mechanisms of action. However, they all inhibit mitochondrial function, a seemingly unique feature among chemotherapeutic drugs. In vitro in variou s cell lines and primary cultures of patient tumor cells and in vivo in var ious rumor models, CHS 828 has cytotoxic properties unlike any of the stand ard cytotoxic drugs with which it has been compared. Among these are non-cr oss-resistance to standard drugs and pronounced activity in tumor models ac knowledged to be highly drug-resistant. Similar to MIBG, CHS 828 induces an early increase in extracellular acidification, due to stimulation of the g lycolytic flux. Furthermore, ATP levels decrease, and the syntheses of DNA and protein are shut off after approximately 30 hr of exposure, indicating active cell death. CHS 828 is now in early clinical trials, the results of which are eagerly awaited. (C) 2001 Elsevier Science Inc. All rights reserv ed.