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Anti-angiogenic treatment with linomide as adjuvant to surgical castration in experimental prostate cancer
B Hartley-Asp1, J Vukanovic, I B Joseph
1Pharmacia & Upjohn, Lund, Sweden.
Purpose:
Escape from "castration inhibition," be it surgical or chemically induced, is still the major problem in prostate cancer treatment. New agents that can be given as adjuvant therapy are needed. Linomide has demonstrated both anti-tumor and anti-angiogenic activity with little toxicity in the Dunning R-3327 rat prostate tumor system. Therefore 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 castration to rats bearing the Dunning R-3327 PAP rat prostate tumor and its effect on tumor growth analyzed. Similar experiments, in which Linomide 25 mg./kg./day was given in the drinking water were carried out in rats with the Dunning R-3327 G tumor. The effect of treatment on blood vessel density and blood flow in the tumor was also assessed using an image 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 tumor 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 regrowth of the tumors occurred, either in the same animal or on transplantation to new intact hosts, demonstrating that the tumor cells were still viable. Tumor blood vessel density was decreased both after castration and Linomide treatment alone, 40 and 32% respectively. On combination of castration and Linomide a 60% decrease in blood vessel density was found. This was significantly different from either of the two treatments given alone. The enhancement on combining castration and Linomide was confirmed by a further decrease in blood flow, from 19 and 22 to 12 ml. per minute/gm. tissue respectively.
Conclusions:
Linomide, an anti-angiogenic drug, inhibits escape from "castration inhibition".
Insights
Linomide (roquinimex) effectively inhibits prostate cancer regrowth after castration by reducing tumor blood vessel density. This anti-angiogenic drug shows promise as an adjuvant therapy to overcome treatment resistance.
Area of Science:
- Oncology
- Pharmacology
Background:
- Prostate cancer treatment resistance, particularly escape from castration inhibition, remains a significant clinical challenge.
- Adjuvant therapies are crucial for improving outcomes in prostate cancer management.
Purpose of the Study:
- To investigate the efficacy of Linomide (roquinimex) as an adjuvant therapy in a rat prostate tumor model.
- To assess Linomide's impact on tumor regrowth and angiogenesis in the context of castration.
Main Methods:
- Linomide was administered alone or with castration to rats with Dunning R-3327 PAP and G prostate tumors.
- Tumor growth, blood vessel density, and blood flow were analyzed using image analysis systems.
Main Results:
- Linomide inhibited tumor regrowth after castration in both Dunning R-3327 PAP and G models.
- Combined castration and Linomide treatment significantly decreased tumor blood vessel density (60%) and blood flow compared to monotherapy.
- Tumor cells remained viable after treatment cessation, indicating the need for sustained therapy.
Conclusions:
- Linomide demonstrates significant anti-tumor and anti-angiogenic activity in prostate cancer.
- This drug effectively inhibits escape from castration-induced tumor inhibition, suggesting its potential as an adjuvant therapy.