ABSTRACT
We studied the effects of three newly synthesized steroidal derivatives of nitrogen mustards, alone or in combination with caffeine, on sister chromatid exchange (SCE) frequencies and on human lymphocyte proliferation kinetics. The agents have as alkylator functionalities either P-N,N-bis(2-chloroethyl)aminophenyl-buturate (CHL) or P-N,N-bis(2-chloroethyl)aminophenyl-acetate (PHE), esterified with a modified steroidal nucleus. An enhancement of SCE frequency was seen with compounds which contain either PHE or CHL as alkylators and are esterified with a steroidal nucleus having added a cholestene group in the 17-position of the D-ring. The exocyclic insertion of an -NHCO- group in the D-ring of the steroidal nucleus esterified with PHE (amide ester of PHE) gave a compound showing increased SCE frequency. Enhanced cytogenetic damage was observed when lymphocytes were exposed in vitro to caffeine. The compounds, alone or in combination with caffeine, caused a concentration-dependent increase in SCE frequencies and cell division delays, and caffeine was found to act synergistically with the steroidal alkylators.
Subject(s)
Antineoplastic Agents, Alkylating , Caffeine , Cell Nucleus/metabolism , Central Nervous System Stimulants , Chromosome Aberrations/chemically induced , Lymphocytes/metabolism , Nitrogen Mustard Compounds , Sister Chromatid Exchange/drug effects , Adult , Antineoplastic Agents, Alkylating/adverse effects , Antineoplastic Agents, Alkylating/agonists , Antineoplastic Agents, Alkylating/pharmacology , Caffeine/adverse effects , Caffeine/agonists , Caffeine/pharmacology , Cell Nucleus/genetics , Cell Nucleus/pathology , Central Nervous System Stimulants/adverse effects , Central Nervous System Stimulants/agonists , Central Nervous System Stimulants/pharmacology , Drug Synergism , Female , Humans , Lymphocytes/pathology , Male , Nitrogen Mustard Compounds/adverse effects , Nitrogen Mustard Compounds/agonists , Nitrogen Mustard Compounds/pharmacology , Steroids/adverse effects , Steroids/agonists , Steroids/pharmacologyABSTRACT
INTRODUCTION: Advanced glycation end products (AGEs) engagement of a monocyte surface receptor (RAGE) induces atherosclerosis. AGEs also act as CD36 ligands. We studied reactive oxygen species (ROS) and CD36 expression after siRNA inhibition of RAGE expression in human monocytes. METHODS: We isolated monocytes from: a) 10 type 2 diabetics, and b) 5 age- and sex-matched healthy individuals. CD36 expression and ROS production were evaluated before and after RAGE knockdown. RESULTS: After incubation of monocytes with AGE + bovine serum albumin (BSA), CD36 expression and intracellular ROS increased significantly in all groups. In RAGE-knockdown monocytes, AGE-induced CD36 expression and ROS generation were also significantly inhibited. CONCLUSIONS: Blocking RAGE expression using siRNA in human monocytes led to a significant inhibition of CD36 expression and ROS production, suggesting a positive interaction between RAGE, CD36 expression and ROS generation in monocytes.