Antiproliferative and Cytotoxic Effects of Single and Combined Treatment with Tumor Necrosis Factor α and/or α Interferon on a Human Renal Cell Carcinoma Xenotransplanted into nu/nu Mice: Cell Kinetic Studies

A human renal cell carcinoma serially transplanted into nude mice was treated with recombinant human tumor necrosis factor a (TNF-o), recombinant human α interferon (IFN-α), and a combination of both. All treatments resulted in a significantly reduced tumor growth. The greatest effect was obtained with the combination of TNFα and IFN-α. This latter treatment completely eradicated tumors which were smaller than 50 mm3 at the beginning of treatment. Cell kinetic analysis using the bromodeoxyuridine technique and flow cytometry revealed a prolongation of the transition time through S-phase from 7.9 h in the case of control tumors to 10.5 h for tumors treated with IFN-a and TNF-a. Single treatment with either TNF-α or IFN-α had only minor effects. The bromodeoxyuridine labeling index was unaffected by IFN-α (16.6%; control, 15.2%) but was reduced to 12.1 and 11.7% when tumors were treated with TNF-α and IFN-α plus TNF-α, respectively. The calculated potential doubling times were 23 and 2.8 days, respectively, for tumors treated with TNF-α or IFN-α plus TNF-v. When treated with IFN-α, the potential doubling time (1.7 days) was similar to that of the control (1.6 days), indicating that the main effect of TNF-a was antiproliferative. Conversely, the calculated cell loss factors increased after IFN-a and combined treatment but not after TNF-a treatment. Combined treatment augmented cytotoxicity, but the cell kinetic characteristics of surviving cells remained similar to those of tumors treated with TNF-α alone. Histological analysis showed a distinctly reduced mitotic activity but no coagulative necroses after treatment with TNF-α. IFN-α and, in particular, IFN-α plus TNF-α induced cytoplasmic vacuolization, nuclear pyknosis, and cell death, which resulted in tumor regression. These data suggest that, in this particular tumor model, TNF-α produces mainly antiproliferative effects, whereas IFN-α acts via cytotoxic mechanisms.