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[Therapy of prostate carcinoma with polyamine synthesis inhibitors. I. Physiological and pathophysiological
Abstract:
The therapeutic concept of irreversible inhibition of both ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) by alpha-difluoromethylornithine (DFMO) and methylglyoxal bis-guanylhydrazone (MGBG) is based on pathologic activities of these enzymes in tumor tissue. The polyamines putrescine, spermidine and spermine are measured in highest concentration in the prostate of both men and animals, with a significant increase of spermine in benign hyperplasia of the prostate. Patients with metastatic cancer of the prostate have elevated putrescine levels in the 24-hour urine. Treatment with 3 or 1% DFMO or 11 mg/kg MGBG in transplantable human and experimental cancer of the prostate demonstrated a significant anti-growth effect. A combination of DFMO and MGBG is tumor-destructive. The combination of 1% DFMO and 11 mg/kg MGBG distinctly reduces the activity of ODC and SAMDC and significantly lowers the levels of putrescine, spermidine and spermine in the tumor.
Insights
Alpha-difluoromethylornithine (DFMO) and methylglyoxal bis-guanylhydrazone (MGBG) target key enzymes in polyamine synthesis. This combination shows significant anti-tumor effects in prostate cancer models, reducing enzyme activity and polyamine levels.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Context:
- Polyamines, including putrescine, spermidine, and spermine, are crucial for cell growth and are implicated in prostate cancer.
- Elevated spermine levels are observed in benign prostate hyperplasia, while increased putrescine is found in metastatic prostate cancer patients' urine.
- Ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) are key enzymes in polyamine biosynthesis, often dysregulated in tumors.
Purpose:
- To investigate the therapeutic potential of irreversibly inhibiting ODC and SAMDC using DFMO and MGBG in prostate cancer.
- To evaluate the anti-growth effects of DFMO and MGBG, individually and in combination, on experimental and transplantable prostate cancer models.
- To assess the impact of the combined treatment on ODC and SAMDC activity and polyamine levels within tumors.
Summary:
- DFMO and MGBG were administered to prostate cancer models, demonstrating significant anti-growth effects.
- The combination of DFMO and MGBG exhibited tumor-destructive properties.
- Combined treatment with 1% DFMO and 11 mg/kg MGBG markedly reduced ODC and SAMDC activity and decreased putrescine, spermidine, and spermine levels in tumors.
Impact:
- This study highlights the synergistic anti-cancer effect of combining DFMO and MGBG, suggesting a promising therapeutic strategy for prostate cancer.
- The findings support the targeting of polyamine biosynthesis as a viable approach for managing prostate cancer.
- The reduction in key polyamine levels and enzyme activity underscores the mechanism of action for this combination therapy.