Cure of B 16 F 1 O Melanoma Lung Metastasis in Mice by Chronic Indomethacin Therapy Combined with Repeated Rounds of Interleukin 2 : Characteristics of Killer Cells Generated

Abstract

We had earlier shown that a single round of interleukin 2 (IL-2) in chronically Indomethacintreated mice can totally or nearly totally amel lorate established,experimental lung metastasesand reactivate natural killer (NK) and lymphokine activated killer-like cells in the spleen. The presentstudyexaminedwhethera lasting cureofmetastasis is obtainable by chronic Indomethacin therapy (Cli') combined with single or multiple rounds of IL-2, and if so, what are the morphological, phenotypic,and functional properties oftumoricidal cells generated in situ. Experimental lung metastasis was produced in B6 mice by an Lv. injection of 10' B16FIO melanoma cells to compare therapeutic effects of six protocols: (a) CIT(14 @ig/ml viadrinkingwater)startingonday5 whenpulmonary micrometastases are well established (b) CIT combined with a single round of IL-2 (25,000 units, i.p., every 8 h for 5 days on days 10 through 14) (c) CIT combinedwith two rounds of IL-2 (days 10-14 and 20-24) (d) two roundsof IL-2 alone (e) two rounds of IL-2 plus indomethacin givenonly during the IL-2 therapy and (I) which wassimilar to (c), but in addition, followed by repeatedinjections of IL-2 (25,000 units twice a day on Mondays and Fridays for S consecutiveweeks).Results revealed that chronic Indomethacintherapy alone or two rounds of IL-2 alone, or two rounds of IL-2 plus discontinuousindOmetliaCin therapy reducedthe lung metastases(examinedat 21-25 days) by about two-thirds. In con trast, both singleandmultiple roundsof IL-2 in chronically Indomethacin treated mice totally or nearly totally eradicated the lung metastases. However,long-termdisease-free survival(>13-16 months)resultedonly with multiple rounds of IL-2. With chronic indomethacin therapy alone, NK-like(AGM-1@, Thy-1, Lyt-2) killer lymphocytes(capableof killing NKsensitiveYAC-1lymphomaandB16F1Omelanomatargets)appeared In the spleen,but not lungs no killer activity was generatedin macro phages at either site. Addition of a single round of IL-2 generated lymphokineactivatedkiller-like killer lymphocytes(also capableof killing an NK resistant target) of the same phenotype, but of higher activityin thespleen;somelymphokineactivatedkiller-like killer func don wasgeneratedamongpulmonary lymphocyteswhich wereAGM-1', Thy-i', Lyt-2, as well as amongsplenic but not pulmonaryniacrophages. A repetition of IL-2 therapy in these indomethacin treated animals generated the highest tumoricidal activity for all the targets in splenic and pulmonary lymphocyteswhich expressedAGM-I as well as Thy-i but not Lyt-2. Furthermore, significant killer function was now seen amongsplenic as well as pulmonary macrophages.Injection of AGM-i antibody into thesemice totally annulled the therapeutic effects on lung metastasisas well as killer cell reactivation. These results reveal that chronic indomethacin therapy combined with multiple rounds of IL-2 activates killer cells ofthe broadest spectrum and geographic distribution Including the tumor site to result in a lasting cure of experimental metastasis,AGM-1 bearingcells playing a central role in this cure.

Cite this paper

@inproceedings{Parhar2006CureOB, title={Cure of B 16 F 1 O Melanoma Lung Metastasis in Mice by Chronic Indomethacin Therapy Combined with Repeated Rounds of Interleukin 2 : Characteristics of Killer Cells Generated}, author={Sukhdev Parhar}, year={2006} }