In vivo antitumor efficacy of interleukin-21 in combination with chemotherapeutics.
Interleukin-21 (IL-21) is a class I cytokine with antitumor properties due to enhanced proliferation and effector function of CD8(+) T cells and natural killer (NK) cells. Here we have explored the magnitude and time-course of cytostatics-induced lymphopenia in mice and investigated whether treatment with cytostatics influences the antitumor effect of IL-21 in mouse tumor models. We show that pegylated liposomal doxorubicin (PLD), irinotecan and oxaliplatin induced transient lymphopenia, whereas 5-fluorouracil (5-FU) transiently increased lymphocyte counts. B cells were more sensitive than T cells towards irinotecan and oxaliplatin. Additive antitumor effects were observed after combining IL-21 with PLD, oxaliplatin and to less extent 5-FU but not irinotecan, and larger effect was observed when IL-21 administration was postponed relative to chemotherapy, suggesting that these agents may transiently impair immune function. However, the chemotherapies did not significantly alter the levels of circulating regulatory T cells and only marginally affected the ability of CD8(+) T cells to respond to IL-21 measured as increased granzyme B mRNA. Our results show that IL-21 therapy can be successfully combined with agents from different chemotherapeutic drug classes, i.e. topoisomerase II inhibitors (PLD), anti-metabolites (5-FU) and platinum analogs (oxaliplatin) provided that IL-21 therapy is delayed relative to chemotherapy.
Skak
Kresten
K
Immunopharmacology, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark. skak@novonordisk.com
Søndergaard
Henrik
H
Frederiksen
Klaus Stensgaard
KS
Ehrnrooth
Eva
E
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology*; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D013601:T-Lymphocytes / Q000187:drug effects*; D000098546:Interleukin-21
D000970:Antineoplastic Agents; D007378:Interleukins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D004317:Doxorubicin; D000098546:Interleukin-21; D005472:Fluorouracil; D002166:Camptothecin