STUDIES OF NATURAL-KILLER-CELL ACTIVITY IN A DRUG-FREE, HEALTHY POPULATION - RESPONSE TO A CHALLENGE WITH TAXOL, ESTRAMUSTINE AND LIPOPOLYSACCHARIDE

Preincubation of peripheral blood lymphocytes with the microtubule dis turbing agents estramustine (ETMN; n = 7, final conc. 20 uM) or taxol (TX; n = 13, final cone. 10 uM), resulted in a statistically significa nt inhibition of natural killer cell activity [(NKCA); baseline (x +/- SD; expressed as percentage of specific chromium release) of 32.2 +/- 30.5 and 34.4 +/- 27.7 and drug treated samples of 13.9 +/- 19.9 and 12.5 +/- 20.8, respectively; Student's paired t-test p < 0.005]. Furth ermore, most individual values for NKCA in the drug preincubated sampl es were at least 20% below the same subject baseline lytic function (e xcept for TX sample No. 1), and NKCA was non detectable in 4 out of 7 and 5 out of 13 samples (pretreatment with either ETMN or TX, respecti vely). The use of other concentrations and different preincubation tim es for these chemotherapeutic agents also produced NKCA inhibition, wh ich was time and dose dependent. Preincubation with lipopolysaccharide (LPS; n = 16, final conc. 50 mu g/ml), an endotoxin prominently invol ved in the etiology of septic shock, resulted in a statistically signi ficant enhancement of NKCA [baseline (x +/- SD; expressed as percentag e of specific chromium release) of 25.4 +/- 20.4 and LPS treated sampl e of 36.6 +/- 17.4, respectively; Student' s t paired t-test p < 0.005 ]. At least a 20% increase in NKC lytic function over its own baseline value was recorded for each and everyone of the samples tested with L PS. Addition of TX and further incubation (24h) of peripheral blood ly mphocytes already pretreated (48h) with LPS (n = 6) resulted in statis tically significant NKCA downmodulation [baseline (x +/- SD) and LPS TX treated samples of 36.9 +/- 26.8 and 5.4 +/- 7.4, respectively; St udent's paired t-test p < 0.01]. NKCA of individual samples were at le ast 20% below corresponding baseline values, and similar to those reco rded for the same sample preincubated only with TX. The possible clini cal implication of these results should be carefully considered when p lanning the use of ETMN and TX as chemotherapeutic agents. Similarly, the effects of LPS on NKCA may help to explain some of the pathophysio logy associated with septic shock.