ELEVATED PLASMA-LIPID PEROXIDE CONTENT CORRELATES WITH RAPID PLASMA-CLEARANCE OF ALL-TRANS-RETINOIC ACID IN PATIENTS WITH ADVANCED CANCER

The addition of lipid hydroperoxides greatly accelerates the rate of o xidative catabolism of all-trans-retinoic acid (RA) in human cell micr osomes; hydroperoxy metabolites of the arachidonate cascade are partic ularly active in the microsomal system. We have measured the plasma co ntent of lipid peroxides in cancer patients during the course of thera py with RA, seeking to assess whether a correlation exists between the rate of oxidative catabolism of exogenously administered RA and whole body lipid peroxide levels. The assay used for plasma lipid peroxides is the capacity to react with thiobarbituric acid under specified con ditions; the result is expressed as TBARS (thiobarbituric acid reactiv e substances). RA administration produced its own accelerated clearanc e RA within 72 h. Patients were considered to have ''normal'' or ''rap id'' baseline catabolism of RA if their Day 1 area under RA concentrat ion over time curve was greater or less than 300 ng.h/ml, respectively . The mean plasma TBARS levels were: 12 normal volunteers = 0.14 mu M; 19 ''normal'' RA catabolizers = 0.25 mu M; and 14 ''rapid'' cataboliz ers = 0.82 mu M. P = 0.008 (rapid catabolizers versus normal volunteer s) and 0.05 (rapid catabolizers versus normal catabolizers). Repeat TB ARS determinations were made during the course of therapy in 17 patien ts, all of whom converted to ''rapid'' RA catabolism on therapy. An in crease in plasma TBARS levels greater than or equal to 20% of baseline was observed in 5 of 5 prostate cancer patients and 8 of 12 lung canc er patients treated with continuous RA therapy for 2 and 4 weeks, resp ectively. These observations support the hypothesis that high levels o f lipid peroxides and rapid oxidative catabolism of RA are positively correlated.