The addition of
lipid hydroperoxides greatly accelerates the rate of oxidative catabolism of
all-trans-retinoic acid (RA) in human cell microsomes; hydroperoxy metabolites of the arachidonate cascade are particularly active in the microsomal system. We have measured the plasma content of
lipid peroxides in
cancer patients during the course of
therapy 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 conditions; the result is expressed as
TBARS (
thiobarbituric acid reactive substances). RA administration produced its own accelerated clearance RA within 72 h. Patients were considered to have "normal" or "rapid" baseline catabolism of RA if their Day 1 area under RA concentration over time curve was greater or less than 300 ng.h/ml, respectively. The mean plasma
TBARS levels were: 12 normal volunteers = 0.14 microM; 19 "normal" RA catabolizers = 0.25 microM; and 14 "rapid" catabolizers = 0.82 microM. P = 0.008 (rapid catabolizers versus normal volunteers) and 0.05 (rapid catabolizers versus normal catabolizers). Repeat
TBARS determinations were made during the course of
therapy in 17 patients, all of whom converted to "rapid" RA catabolism on
therapy. An increase in plasma
TBARS levels > or = 20% of baseline was observed in 5 of 5
prostate cancer patients and 8 of 12
lung cancer patients treated with continuous RA
therapy for 2 and 4 weeks, respectively. These observations support the hypothesis that high levels of
lipid peroxides and rapid oxidative catabolism of RA are positively correlated.