EFFECTS OF INDOMETHACIN ON LYMPHOKINE-ACTIVATED KILLER-CELL ACTIVITIES IN CANCER-PATIENTS

Prostaglandin E(2) (PGE(2)) is known to downregulate the generation of lymphokine-activated killer (LAK) cell activity. Indomethacin, an inh ibitor of cyclooxygenase catalyzing the biosynthesis of PGE(2), has be en shown to augment LAK cell activities generated from peripheral bloo d mononuclear cells of normal healthy individuals. This study was unde rtaken to examine whether or not this augmentation is also a common ph enomenon in cancer patients. LAK cell activities generated in the pres ence and the absence of indomethacin were examined in 15 normal health y individuals and in 83 cancer patients. Paired data analysis revealed that indomethacin exhibited a significant augmentation of LAK activit y generated from healthy individuals. Indomethacin enhanced LAK activi ty in patients with no distant metastases (T(x)N(x)M(0)); but depresse d LAK activity in patients with distant metastases (T(x)N(x)M(1)). In patients without distant metastases, indomethacin showed an upregulati ng effect on LAK activity in those with an early T stage (T(1-2)N(x)M( 0)), and no such effect was detected in those with a late T stage (T(3 -4)N(x)M(0)). Indomethacin also significantly enhanced LAK cell genera tion in cancer patients with an ECOG performance status of I, but sign ificantly inhibited LAK cell generation in patients with a performance status of 4. These results indicated that indomethacin inhibited gene ration of LAR cell activity in cancer patients with a poor performance status or with distant metastatic disease, who normally would be the subjects of adoptive immunotherapy. Further, PGE(2) production in cult ured LAK cell medium was suppressed by indomethacin in all 20 cancer p atients that were examined, suggesting that other yet to be identified factors or mechanisms may be responsible for the paradoxical effects of indomethacin on LAK cell activity.