Antitumor effects of interleukin-2 and mismatched double-stranded RNA, individually and in combination, against a human malignant melanoma xenograft.
The antitumor effects of recombinant interleukin-2 (rIL-2) and mismatched double-stranded RNA (dsRNA) were assessed in tissue culture and in a nude mouse model. Mismatched dsRNA did not show a direct antiproliferative effect against the human malignant melanoma cell line, BRO, in tissue culture. However, treatment of the BRO cells with up to 1000 units/ml rIL-2 in culture showed a slight increase in growth rate. Combined rIL-2/mismatched dsRNA treatment also demonstrated a similar slight enhancement of growth. Nude mice bearing subcutaneous tumors were treated by intraperitoneal injection of low doses (5000-20,000 units) of rIL-2 and mismatched dsRNA (500 micrograms). The in vivo tumor growth was significantly inhibited by the combined treatments (P less than 0.05) and survival was significantly increased (P less than 0.05). Measurement of cytotoxicity using splenocytes from treated animals showed significant augmentation of lytic activity against natural killer (NK)-sensitive YAC-1 cells in all rIL-2/mismatched dsRNA treatment groups, compared to the individual treatments or controls (P less than 0.05). Cytotoxicity of the splenocytes against the NK-resistant BRO cells was also augmented in animals treated with mismatched dsRNA and the highest rIL-2 dose utilized here (P less than 0.01). Renal, liver, and hematological toxicity was evaluated by measurement of blood urea nitrogen, creatinine, serum asparrtate aminotransferase, and a complete blood count with differential. There were no significant differences in these parameters in any of the treatment groups. Similarly, no differences in weight of the animals was seen in any treatment group. These results indicate that the combination of low-dose rIL-2 and mismatched dsRNA can potentiate host-mediated antitumor effects, yielding increased survival, without significant toxicity.
Hubbell
H R
HR
Department of Neoplastic Diseases, Hahnemann University, Philadelphia, Pennsylvania 19102.
Vargas
H E
HE
Tsujimoto
K L
KL
Gibson
G D
GD
Pequignot
E C
EC
Bigler
R D
RD
Carter
W A
WA
Strayer
D R
DR
D000818:Animals; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D008545:Melanoma / Q000628:therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D012330:RNA, Double-Stranded / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D012330:RNA, Double-Stranded; D011994:Recombinant Proteins