Isolation and characterization of a metastatic Eb-like tumor variant highly responsive to interleukin (IL)-2 and to combination cytokine therapy with IL-2/IL-1 beta and IL-1 beta/interferon-alpha/beta.
In this study, we describe the origin and characterization of a new metastatic tumor cell line (p11-R-Eb) obtained after i.p. passages of the nonmetastatic Eb lymphoma cells into DBA/2 mice. The p11-R-Eb cells exhibited the same morphology and in vitro growth properties and chromosome markers as the original Eb cells. FACS analysis of the p11-R-Eb cells also revealed a close similarity to the Eb cells. Moreover, the p11-R-Eb cells were specifically killed by anti-Eb cytotoxic lymphocytes. In spite of all these characteristics of the Eb line, p11-R-Eb cells metastasized to the liver when injected i.v. or s.c. in DBA/2 mice. Peritumoral interleukin (IL)-2 treatment resulted in a potent antitumor response in DBA/2 mice transplanted s.c. with p11-R-Eb cells. In contrast, the same IL-2 regimen did not significantly increase the survival time of mice transplanted with the highly metastatic ESb cell line. Combined IL-1/IL-2 treatments of established p11-R-Eb tumors resulted in a synergistic antitumor effect and in tumor regression in 70% of the injected mice. Similarly, combined peritumoral treatment with IL-1 and interferon-alpha/beta, which were poorly effective or ineffective as single cytokine therapy, resulted in a marked antitumor effect, and 30% of the mice were cured. Spleen cells from IL-1/IL-2-treated p11-R-Eb-cell-injected mice showed a marked antitumor activity when assayed in a Winn assay with homologous tumor cells. This antitumor activity was eliminated by preincubation of spleen cells with antibodies to CD4 and complement and markedly inhibited by anti-asialo GM1 antibodies. P11-R-Eb cells represent, therefore, a new tumor model which may be useful for investigating the relevant mechanisms which need to be activated to achieve a potent antitumor response to cytokine therapy in the DBA/2 mouse host.
Gabriele
L
L
Istituto Superiore di Sanità, Rome, Italy.
Proietti
E
E
Greco
G
G
Venditti
M
M
Gresser
I
I
Schirrmacher
V
V
Von Hoegen
P
P
Testa
U
U
Modesti
A
A
Cianfriglia
M
M
D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D000954:Antigens, Surface / Q000032:analysis; D016207:Cytokines / Q000494:pharmacology*; D003601:Cytotoxicity Tests, Immunologic; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007621:Karyotyping; D008223:Lymphoma / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008854:Microscopy, Electron; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology
D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D016207:Cytokines; D016898:Interferon-alpha; D007375:Interleukin-1; D007376:Interleukin-2; D016899:Interferon-beta