Enhanced immune system activation after treatment with novel antineoplastic platinum agents.
"Poly-plat", SSP, and SAP are second generation analogs of cisplatin (CDDP) with higher efficacy and potency. In order to understand the mechanism of action of these compounds, isolated murine peritoneal macrophages were treated with "poly-plat", SSP, or SAP (5 micrograms/ml) for 2 h. Treated macrophages demonstrated an increase in the number of lysosomes, but only "poly-plat" and SSP treated macrophages were stimulated to form the cytoplasmic extensions so very characteristic of cisplatin after 2 h and 24 h post-treatment. SAP showed cytoplasmic extensions only after 24 h post-treatment, and demonstrated a back to the normal discoid form when viewed at 24 h post-treatment. When drug treated macrophages were co-incubated with S180 tumor cells, cytoplasmic extensions of the macrophages developed contacts, and cytoplasmic continuity with the tumor cells, and a subsequent transfer of lysosomes from macrophage to tumor cell was observed after only 2 h of co-incubation. After 24 h of co-incubation, lysis of S180 cells was achieved. Analysis of the tissue culture supernatants collected from "poly-plat", SSP, and SAP treated macrophages demonstrated the enhanced activity of interleukin-1 alpha of over 400 pg/ml after 2 h post-treatment, compared to only 300 pg/ml with cisplatin 24 h post-treatment. However, only SSP demonstrated an increase in TNF-alpha activity (2000 pg/ml) after 2 h post-treatment, which is comparable to that of cisplatin. Based on our observations we propose that "poly-plat", SSP, and SAP activate various cytolytic factors of the immune system better, than cisplatin.
Muenchen
H J
HJ
Department of Zoology, Michigan State University, East Lansing 48824-1115, USA.
Aggarwal
S K
SK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002945:Cisplatin / Q000031:analogs & derivatives / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects / Q000502:physiology; D007375:Interleukin-1 / Q000096:biosynthesis; D007700:Kinetics; D008247:Lysosomes / Q000187:drug effects / Q000648:ultrastructure; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D051379:Mice; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors
C113947:4-hydroxy-sulfonylphenylacetato-(1,2-diaminocyclohexane) platinum; C113946:5-sulfosalicylato-(1,2-diaminocyclohexane) platinum; D000970:Antineoplastic Agents; D007375:Interleukin-1; D009573:Nitrites; D009944:Organoplatinum Compounds; C111406:poly(trans-1,2-diaminocyclohexane)platinum-carboxyamylose; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D002945:Cisplatin