Dualistic effects of cis-diammine-dichloro-platinum on the anti-tumor efficacy of subsequently applied recombinant interleukin-2 therapy: a tumor-dependent phenomenon.
The efficacy with which disseminated SL2 and P815 tumors, in syngeneic DBA/2 mice, can be eradicated with low-dose recombinant interleukin-2 (rIL-2) therapy is about equal. Treatment (i.p.) of DBA/2 mice, injected i.p. with SL2 or P815 cells on day 0, with rIL-2 (Proleukin) on days 10 to 14 results in a cure rate of 50 to 60% in each case. The in vitro sensitivity of SL2 and P815 cells to cis-diammine-dichloro-platinum [II] (cisplatin) is also comparable, although P815 appears to be slightly more sensitive. In vivo, however, therapy with cisplatin is far less effective against P815 than against SL2. In the DBA/2-SL2 model, at all doses tested, combination therapy with cisplatin (administered on day 2) and rIL-2 (administered on days 10-14) resulted in anti-tumor efficacy greater than that of either drug separately. In contrast, in the DBA/2-P815 model, cisplatin decreased the anti-tumor efficacy of subsequently applied rIL-2 therapy. As the only difference between the 2 tumor models is the tumor itself, the success of combination therapy with cisplatin and rIL-2 was dependent on tumor characteristics. We suggest that in these 2 tumor models, neither the sensitivity of these tumors to cisplatin nor their growth and dissemination patterns were responsible for the contrasting results of combination therapy in these models. Instead, tumor-dependent immune-modulating effects of cisplatin may be the cause of these effects. These immune-modulating effects may comprise (a) effects of cisplatin on the tumor cells, resulting in changes in their susceptibility to immune effector cells, or changes in their immunogenicity; (b) activating or suppressive effects of cisplatin on immune effector cells; or (c) a combination of these effects. These effects could then either synergize or antagonize with the immune activating properties of rIL-2.
Department of Obstetrics and Gynecology, University Hospital, Utrecht, The Netherlands.
M R
MR
Bernsen
H J
HJ
Van Barlingen
A W
AW
Van der Velden
H F
HF
Dullens
W
W
Den Otter
A P
AP
Heintz
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D007109:Immunity / Q000187:drug effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology; D012515:Mast-Cell Sarcoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA
D007376:Interleukin-2; D002945:Cisplatin