Tumor growth and tumor radiosensitivity in mice given myeloprotective doses of fibroblast growth factors.

Abstract

Radiation at doses high enough to cure cancer also frequently destroys normal tissue. Development of agents that protect normal tissue without also protecting diseased tissue has been difficult. In vivo radioprotection of bone marrow by acidic and basic fibroblast growth factors (FGF1 and FGF2, respectively) has recently been demonstrated after whole-body irradiation of C3H/HeN mice. Our purpose was to determine whether myeloprotective doses of those growth factors also protect malignant tumors. First, we investigated the effects of exogenous FGF1 or FGF2 (FGF1/2) administration (treatment group receiving two intravenous injections of 3 micrograms FGF1/2 per mouse 24 hours and 4 hours before local irradiation of right hind leg and control group receiving two intravenous injections of 0.1 mL of saline) on growth and radiosensitivity of three transplantable murine tumors (one squamous cell carcinoma [SCC-VII] and two sarcomas [KHT and Rif-1]), all of which were grown in C3H/HeN mice. We then evaluated the effect of FGF1/2 on tumor cell proliferation, cell cycle distribution, and pulmonary metastatic frequency in the mice. Specifically, survival studies were performed in mice treated with 0, 6, 6.5, 7.5, 8.5, 9, or 10 Gy whole-body irradiation with or without FGF2 (n = 250). Rif-1 (n = 40), KHT (n = 40), and SCC-VII (n = 40) tumors were implanted in the hind leg of mice, and mice were treated with FGF2 or saline when their tumor-bearing thighs were 9 mm in diameter. In separate experiments (treatment group receiving two injections of 3 micrograms each of FGF2 [6 micrograms total] either intravenously or intratumorally 24 hours and 4 hours before local tumor irradiation and control group receiving 0.1 mL saline), tumor growth was followed, and mice were killed to count lung metastases and measure tumor proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine labeling at various times thereafter (three to eight mice per group). Tumor growth curves of untreated and irradiated tumors were determined with and without intravenous or intratumoral FGF1/2 in SCC-VII tumors (n = 120). Radiation doses to the tumor-bearing leg were 15 and 30 Gy for SCC-VII, 30 Gy for Rif-1, and 15 Gy for KHT. From each experiment, the mean (+/- 1 standard error) was calculated from data obtained from three to 20 mice. Statistical tests used included two-tailed Student's t test, the chi-squared test, and Fisher's exact test. All P values represent two-tailed tests of statistical significance. There was no statistically significant difference in tumor growth rate between FGF2-treated and saline-treated mice when FGF2 was administered intravenously at doses and schedules found to be optimally myeloprotective in whole-body irradiation experiments. Intravenous administration of FGF2 did not induce lung metastases, and it did not augment the S-phase fraction of tumor cells. Likewise, there was no evidence of enhanced cell proliferation as measured by PCNA-labeling index. Intratumoral injection of FGF1/2 did increase the size of SCC-VII tumors (P < .05 [Student's t test] at 3 days after treatment); however, the radiation response after intratumoral injection of growth factor was not compromised. Low intravenous doses of FGF1 or FGF2 appear to protect bone marrow from the toxic effects of radiation without increasing the rates of tumor growth or metastases or decreasing the radiosensitivity of tumors.