ANTI-ANGIOGENIC TREATMENT WITH LINOMIDE AS ADJUVANT TO SURGICAL CASTRATION IN EXPERIMENTAL PROSTATE-CANCER

Purpose: Escape from ''castration inhibition,'' be it surgical or chem ically induced, is still the major problem in prostate cancer treatmen t. New agents that can be given as adjuvant therapy are needed. Linomi de has demonstrated both anti-tumor and anti-angiogenic activity with little toxicity in the Dunning R-3327 rat prostate tumor system. There fore it was deemed essential to study the efficacy of this drug in the adjuvant situation. Materials and Methods: Linomide, roquinimex, was administered 3 times a week i.p. alone or in conjunction with castrati on to rats bearing the Dunning R-3327 PAP rat prostate tumor and its e ffect on tumor growth analyzed. Similar experiments, in which Linomide 25 mg./kg./day was given in the drinking water were carried out in ra ts with the Dunning R-3327 G tumor. The effect of treatment on blood v essel density and blood now in the tumor was also assessed using an im age analysis system. Results: Linomide, 2.5 & 40 mg./kg., administered from the day after castration inhibited the regrowth of the Dunning R -3327 PAP tumors In addition, Linomide 40 mg./kg. administered after t umor regrowth occurred following castration(week 10) inhibited further tumor growth. Inhibition of tumor regrowth after castration was also found in the Dunning G tumor. When Linomide treatment was stopped regr owth of the tumors occurred, either in the same animal or on transplan tation to new intact hosts, demonstrating that the tumor cells were st ill viable. Tumor blood vessel density was decreased both after castra tion and Linomide treatment alone, 40 and 32% respectively. On combina tion of castration and Linomide a 60% decrease in blood vessel density was found. This was significantly different from either of the two tr eatments given alone. The enhancement on combining castration and Lino mide was confirmed by a further decrease in blood now, from 19 and 22 to 12 mi. per minute/gm. tissue respectively. Conclusions: Linomide, a n anti-angiogenic drug, inhibits escape from ''castration inhibition.' '