Related Experiment Videos
[Therapy with inhibitors of polyamine biosynthesis in refractory prostatic carcinoma. An experimental and clinical
Abstract:
Transplantable prostate adenocarcinoma were treated with polyamine biosynthetic inhibitors. alpha-difluoromethylornithine (alpha-DFMO), an inhibitor of ornithine decarboxylase and by s-methylglyoxal-bisguanylhydrazone (MGBG), an inhibitor of s-adenosylmethionine decarboxylase. The therapeutic regimen of 0.8-1.11 g/kg DFMO reduced the tumor growth by 40% whilst the combination with 10.5 mg/kg MGBG completely destroyed the prostate adenocarcinomas in the tumor-bearing animals. The polyamine content of spermidine and spermine in the cancerous tissues is significantly lower whereas the putrescine levels remain unchanged. The MGBG therapy distinctly stimulates the activity of ornithine decarboxylase and increases the putrescine concentration up to toxic levels. The application of alpha-DFMO prevented the toxic accumulation of putrescine and allowed higher doses of MGBG. Clinical trials with polyamine antimetabolites appeared useful due to pathological polyamine excretion of patients with metastatic prostate cancer. The therapy with 0.2-0.3 g/kg DFMO in patients with hormone-resistent prostate cancer and metastasis displayed a moderate anti-tumor activity following 2 months additional treatment. High levels of side effects, however, were registered and were similar to those of other cytotoxic compounds. A combined therapy with DFMO/MGBG in a patient with metastatic anaplastic prostate cancer did not improve the survival rate but showed regressive effects of the histological pattern.
Insights
Polyamine inhibitors alpha-difluoromethylornithine (DFMO) and s-methylglyoxal-bisguanylhydrazone (MGBG) showed significant anti-tumor effects in prostate cancer models. Combination therapy completely eradicated tumors in animals, with DFMO mitigating MGBG toxicity.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Prostate cancer is characterized by altered polyamine metabolism.
- Polyamines are crucial for cell growth and proliferation.
- Inhibiting polyamine biosynthesis is a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the efficacy of polyamine biosynthetic inhibitors, alpha-difluoromethylornithine (DFMO) and s-methylglyoxal-bisguanylhydrazone (MGBG), in treating prostate adenocarcinoma.
- To investigate the effects of DFMO and MGBG, alone and in combination, on tumor growth and polyamine levels.
- To assess the clinical utility of polyamine antimetabolites in patients with metastatic prostate cancer.
Main Methods:
- Treatment of transplantable prostate adenocarcinoma with DFMO (ornithine decarboxylase inhibitor) and MGBG (s-adenosylmethionine decarboxylase inhibitor).
- Assessment of tumor growth reduction, tumor eradication, and polyamine content (spermidine, spermine, putrescine) in cancerous tissues.
- Clinical trials with DFMO in patients with hormone-resistant prostate cancer and metastasis, and a combined DFMO/MGBG therapy in a patient with metastatic anaplastic prostate cancer.
Main Results:
- DFMO (0.8-1.11 g/kg) reduced tumor growth by 40%.
- Combination therapy with DFMO and MGBG (10.5 mg/kg) completely destroyed prostate adenocarcinomas in animals.
- MGBG alone increased ornithine decarboxylase activity and putrescine levels to toxic levels, which was prevented by DFMO.
- Clinical DFMO therapy (0.2-0.3 g/kg) showed moderate anti-tumor activity but significant side effects.
- Combined DFMO/MGBG therapy in one patient did not improve survival but showed histological regression.
Conclusions:
- Polyamine biosynthetic inhibitors demonstrate significant anti-tumor potential in prostate cancer.
- Combination therapy with DFMO and MGBG offers a promising strategy for complete tumor eradication in preclinical models.
- DFMO can mitigate MGBG-induced toxicity, allowing for higher therapeutic doses.
- Clinical application of polyamine antimetabolites warrants further investigation, particularly regarding side effect management and combination strategies.