Radiation therapy to a primary tumor accelerates metastatic growth in mice

The surgical removal of a primary tumor can result in the rapid growth of m etastases, The production of angiogenesis inhibitors by the primary tumor i s one mechanism for the inhibition of metastatic tumor growth. The effect o f curative radiotherapy to a primary tumor known to make an inhibitor of an giogenesis and the effects on distant metastases has not been studied. We h ere show that the eradication of a primary Lewis lung carcinoma (LLC-LM), w hich is known to generate angiostatin, is followed by the rapid growth of m etastases that kill the animal within 18 days after the completion of radia tion therapy. The right thighs of C57BL/6 mice (n = 25) were injected s.c. with 1 x 10(6) LLC-LM cells. Animals were randomized to one of five groups: no irradiation, 40 Gy in one Fraction, 30 Gy in one fraction, 40 Gy in two 20 Gy fractions, or 50 Gy in five 10 Gy fractions. Tumors were clinically eradicated in each treatment group. Ail of the surviving animals became dys pneic and were killed within 14-18 days after the completion of radiation t herapy. Examination of their lungs revealed >46 (range, 46-62) surface meta stases in the treated animals compared with 5 (range, 2-8) in the untreated animals. The lung weights had increased from 0.2 g (range. 0.19-0.22 g) in the controls to 0.58 g (range 0.44-0.84) in the experimental animals, The most effective dose regimen was 10 Gy per fraction for five fractions, and serial experiments were conducted with this fractionation scheme. Complete response of the primary tumor was seen in 25 of 35 (71%) mice. The average weight of the lungs in the nonirradiated animals was 0.22 g (range. 0.19-0. 24 g) and in the irradiated animals was 0.66 g (range, 0.61-0.70 g). The av erage number of surface metastases increased from five per lung (range, 2-1 3) in the control animals to 53 per lung (range. 46-62) in the irradiated a nimals. Both differences were statistically significant with P < 0.001. If the nontumor-bearing leg was irradiated or the animals were sham-irradiated , no difference in the number of surface metastases or lung weights was obs erved between the control group and the treated group. Urinary levels of ma trix metalloproteinase 2, the enzyme responsible fur angiostatin processing in this tumor model, were measured and correlated with the viability and s ize of the primary tumor. Administration of recombinant angiostatin prevent ed the growth of the metastases after the treatment of the primary tumor. I n this model, the use of radiation to eradicate a primary LLC-LM tumor resu lts in the growth of previously dormant lung metastases and suggests that c ombining angiogenesis inhibitors with radiation therapy may control distant metastases.