| In Vitro | In vitro activity: Procarbazine plus Cu(II) induce piperidine-labile and formamidopyrimidine-DNA glycosylase-sensitive lesions at the 5'-ACG-3' sequence, complementary to a hotspot of the p53 gene, and the 5'-TG-3' sequence. Procarbazine causes DNA damage through non-enzymatic formation of the Cu(I)-hydroperoxo complex and methyl radicals. Procarbazine has a strong clastogenic effect in hematopoietic cells and is mutagenic in a variety organs after high dose treatment.
Cell Assay: Following Procarbazine or metabolite treatment, cells are diluted to 50.000/mL in 25-cm2
culture flasks (10 mL). Every 24 h, a 0.5-mL aliquot is removed,
diluted 20-fold in Hematall isotonic diluent, and the cell number
determined with a Coulter Model F electronic cell counter. Counts
greater than 10,000/0.5 mL are corrected for coincidence. Cells are
diluted in fresh culture media when cell density exceeded 1 × 106/mL. Cultures are maintained until the aggregate cell number approached 100 × 106/mL and doubling time has returned to 12 h. Cell survival is determined using Equation A, where TD(doubling time for cells of interest) is 12 h. |
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| In Vivo | Procarbazine causes significant decrease in testicular and epididymal weight and a drastic reduction in haploid cells and spermatogenic arrest, demonstrating variation among the test golden hamster. Procarbazine produces a dose-dependent potentiation of MAO A in brown adipose tissue, the elevation being more pronounced following monomethylhydrazine, with activity rising to 350% of that in control homogenates in rats. Procarbazine or monomethylhydrazine reduces metabolism of this amine by a similar degree as had been determined ex-vivo in blood vessel homogenates. Procarbazine is mutagenic, clastogenic and teratogenic in a wide range of test systems of varying complexity and a wide-spectrum carcinogen in rodents and monkeys, causing tumours of the haemopoietic system, the mammary gland, the lung and the nervous system. Procarbazine in vivo undergoes a complex series of metabolic changes that result in the generation of a number of chemically reactive species, including methylating agents and free radicals. |
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