The effect of combining recombinant human tumor necrosis factor-alpha with local radiation on tumor control probability of a human glioblastoma multiforme xenograft in nude mice.

PURPOSE

To evaluate the antitumor activity of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) on a human glioblastoma multiforme (U87) xenograft in nude mice, and to study the effect of combining rHuTNF-alpha with local radiation on the tumor control probability of this tumor model.

METHODS AND MATERIALS

U87 xenograft was transplanted SC into the right hindleg of NCr/Sed nude mice (7-8 weeks old, male). When tumors reached a volume of about 110 mm3, mice were randomly assigned to treatment: rHuTNF-alpha alone compared with normal saline control; or local radiation plus rHuTNF-alpha vs. local radiation plus normal saline. Parameters of growth delay, volume doubling time, percentage of necrosis, and cell loss factor were used to assess the antitumor effects of rHuTNF-alpha on this tumor. The TCD50 (tumor control dose 50%) was used as an endpoint to determine the effect of combining rHuTNF-alpha with local radiation.

RESULTS

Tumor growth in mice treated with a dose of 150 micrograms/kg body weight rHuTNF-alpha, IP injection daily for 7 consecutive days, was delayed about 8 days compared to that in controls. Tumors in the treatment group had a significantly longer volume doubling time, and were smaller in volume and more necrotic than matched tumors in control group. rHuTNF-alpha also induced a 2.3 times increase of cell loss factor. The administration of the above-mentioned dose of rHuTNF-alpha starting 24 h after single doses of localized irradiation under hypoxic condition, resulted in a significant reduction in TCD50 from the control value of 60.9 Gy to 50.5 Gy (p < 0.01).

CONCLUSION

rHuTNF-alpha exhibits an antitumor effect against U87 xenograft in nude mice, as evidenced by an increased delay in tumor growth as well as cell loss factor. Also, there was an augmentation of tumor curability when given in combination with radiotherapy, resulting in a significantly lower TCD50 value in the treatment vs. the control groups.