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The Journal of Pharmacy and Pharmacology Jun 1992Procarbazine (N-isopropyl-alpha-(2-methyl hydrazino)-p-toluamide hydrochloride) inhibited more powerfully the deamination of benzylamine by semicarbazide-sensitive amine...
Procarbazine (N-isopropyl-alpha-(2-methyl hydrazino)-p-toluamide hydrochloride) inhibited more powerfully the deamination of benzylamine by semicarbazide-sensitive amine oxidase (SSAO) of rat brown adipose tissue than the deamination of 5-hydroxytryptamine and benzylamine by rat liver monoamine oxidase-A or -B activities, respectively. Inhibition of SSAO, but not monoamine oxidase, was time-dependent. Use of metabolic inhibitors, and an enzyme dilution technique, suggested that any conversion of procarbazine to an active species must be as a result of the action of SSAO itself and not of any other enzyme. The non-competitive kinetics and the time-dependence of inhibition were indicative of a suicide interaction between procarbazine and SSAO. The slow reversal of inhibition by dialysis was evidence in favour of the involvement of tight binding, rather than covalent bonding. High concentrations of benzylamine afforded the enzyme significant protection from the action of procarbazine, indicating that the interaction is at or near the active site. If the properties of procarbazine, evident in in-vitro studies, are retained in-vivo, these data suggest that procarbazine might be suitable for the examination of SSAO activities, both in-vivo and ex-vivo.
Topics: Adipose Tissue, Brown; Amine Oxidase (Copper-Containing); Animals; Benzylamines; Carbon Radioisotopes; In Vitro Techniques; Liver; Oxidoreductases Acting on CH-NH Group Donors; Procarbazine; Rats
PubMed: 1359073
DOI: 10.1111/j.2042-7158.1992.tb03652.x -
Archives of Andrology 2002The response of hamster testis to the administration of 450mg/kg procarbazine (PCB) over a period of 4 weeks was evaluated. Flow cytometry was used to investigate...
The response of hamster testis to the administration of 450mg/kg procarbazine (PCB) over a period of 4 weeks was evaluated. Flow cytometry was used to investigate changes in cell populations in testicular single cell suspensions and to correlate these changes with those observed in histological sections. PCB caused significant decrease in testicular and epididymal weight and a drastic reduction in haploid cells and spermatogenic arrest, demonstrating variation among the test animals. The results obtained confirm previous observations concerning detrimental effects of PCB upon spermatogenesis in species such as the rat and mouse, though its effect on hamster testis is milder and does not include the germinal stem cells. The histological evaluation of the testis showed a good correlation with flow cytometric evaluation, emphasizing the usefulness of this method in providing quantitative and rapid results.
Topics: Animals; Cricetinae; Flow Cytometry; Male; Mesocricetus; Procarbazine; Spermatogenesis; Testis
PubMed: 11868631
DOI: 10.1080/014850102317267391 -
Journal of Neurosurgery Mar 1974
Topics: Adolescent; Adult; Anticonvulsants; Astrocytoma; Brain Neoplasms; Child; Electroencephalography; Ependymoma; Evaluation Studies as Topic; Female; Glioblastoma; Glioma; Glucocorticoids; Humans; Immunosuppression Therapy; Leukopenia; Male; Medulloblastoma; Middle Aged; Neoplasm Metastasis; Oligodendroglioma; Procarbazine; Radionuclide Imaging; Thrombocytopenia
PubMed: 4360491
DOI: 10.3171/jns.1974.40.3.0365 -
Journal of Veterinary Internal Medicine 2007Granulomatous meningoencephalomyelitis (GME) is an idiopathic inflammatory disease of the central nervous system. Remission often is short-lived in dogs treated with...
BACKGROUND
Granulomatous meningoencephalomyelitis (GME) is an idiopathic inflammatory disease of the central nervous system. Remission often is short-lived in dogs treated with glucocorticoids. Procarbazine is T cell-specific and crosses the blood-brain barrier.
HYPOTHESIS
Dogs with presumptive antemortem diagnosis of GME given procarbazine as adjunctive therapy to prednisone will have improved long-term outcome compared with dogs given no treatment or glucocorticoids alone.
ANIMALS
Two groups were studied: (1) Dogs with presumptive antemortem diagnosis of GME treated with procarbazine and prednisone (n = 21); (2) Dogs that had a histologic diagnosis of GME at postmortem examination and received no treatment (n = 11).
METHODS
Dogs with presumptive GME treated with procarbazine were identified retrospectively from medical records of 2 veterinary referral hospitals. Selection criteria required all dogs have a neurologic examination, blood work, cerebrospinal fluid analysis, and brain imaging (MRI or CT).
RESULTS
Median survival time for all dogs studied was 5.0 months. Median survival time for dogs treated with procarbazine was 14.0 months and for untreated dogs, 0.73 months. Treatment with procarbazine was significantly correlated with survival time (P < .001). Procarbazine was the only independent predictor of survival. Prednisone was reduced in dosage or discontinued in 17 dogs. Adverse reactions to procarbazine therapy included myelosuppression in 7 dogs and hemorrhagic gastroenteritis in 3 dogs.
CONCLUSION
These data suggest that procarbazine treatment of presumptive GME may result in greater improved long-term outcome than has been previously reported for glucocorticoid treatment alone and may complement other immunomodulatory therapies. Procarbazine-treated dogs must be monitored for adverse reactions.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Dog Diseases; Dogs; Drug Therapy, Combination; Meningoencephalitis; Prednisone; Procarbazine; Retrospective Studies
PubMed: 17338156
DOI: 10.1892/0891-6640(2007)21[100:paatft]2.0.co;2 -
Life Sciences Mar 1978
Topics: Animals; Azo Compounds; Biotransformation; Free Radicals; Male; Microsomes, Liver; Procarbazine; Rats
PubMed: 642707
DOI: 10.1016/0024-3205(78)90358-2 -
Journal of Neurosurgery Oct 1996The authors provided procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy to 32 patients whose tumors contained varying mixtures of oligodendroglial and...
The authors provided procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy to 32 patients whose tumors contained varying mixtures of oligodendroglial and astrocytic cells. Twenty-five patients had oligodendroglioma-astrocytoma (oligoastrocytoma) with a histological Grade of III (19 patients) or IV (six patients); seven had anaplastic oligodendroglioma. The PCV therapy was administered every 6 weeks for a total of at least 124 cycles. The median duration of follow-up review from the start of chemotherapy was 19.3 months. Nineteen patients were treated before receiving radiation therapy and 12 after receiving it (one patient received concurrent radiotherapy and chemotherapy). Grade 3 or 4 hematological toxicity was experienced by nine (31%) of 29 patients. Ten patients had delayed treatment due to treatment-related toxicities (34.5%). Ninety-one percent of the 32 patients responded to the therapy. These included 10 patients with a complete response and 19 with a partial response. The median time to progression was 15.4 months for all patients and 23.2 months for those with Grade III tumors. The median time to progression for patients with Grade III oligoastrocytomas was 13.8 months; for those with Grade IV oligoastrocytoma it was 12.4 months and for those with anaplastic oligodendrogliomas it was 63.4 months (p = 0.0348). These patients survived a median of 49.8 months, 16 months, and 76 or more months, respectively, from the start of chemotherapy (p = 0.0154). The PCV therapy provides durable responses in patients with Grade III or IV oligoastrocytomas.
Topics: Adult; Astrocytoma; Brain Neoplasms; Female; Humans; Lomustine; Male; Middle Aged; Procarbazine; Prognosis; Time Factors; Vincristine
PubMed: 8814163
DOI: 10.3171/jns.1996.85.4.0602 -
Mutation Research Aug 1999Procarbazine, a drug used for cancer chemotherapy, is carcinogenic in rodent bioassays. We analyzed the mutagenicity of procarbazine in various organs and the...
Procarbazine, a drug used for cancer chemotherapy, is carcinogenic in rodent bioassays. We analyzed the mutagenicity of procarbazine in various organs and the clastogenicity of the drug in hematopoietic cells of the lacZ transgenic MutaMouse. This was part of the second collaborative study of the Mammalian Mutagenesis Study Group of the Japanese Environmental Mutagen Society on the transgenic mouse mutation assay. At 50 mg kg(-1), procarbazine induced micronuclei in hematopoietic cells, but it did not increase the lacZ mutant frequency (MF) in bone marrow. It was also negative in liver, testis, spleen, kidney, and lung. Five daily administrations of 150 mg kg(-1) yielded highly positive responses in the drug's target organs for carcinogenesis (lung, bone marrow, and spleen). Lower positive responses were detected in kidney, which is a minor target organ. Liver showed only a slight increase in lacZ MF and brain showed no increase. The testis MF more than doubled which suggest that procarbazine is mutagenic to germ cells. Thus, we demonstrated that procarbazine has a strong clastogenic effect in hematopoietic cells and is mutagenic in a variety organs after high dose treatment. The induced MF was especially high in procarbazine's target organs for carcinogenesis, which supports the relevance of the transgenic mouse mutation assay for the assessment of potential genotoxins in vivo.
Topics: Animals; Carcinogens; Lac Operon; Male; Mice; Mice, Transgenic; Micronucleus Tests; Mutagens; Mutation; Organ Specificity; Procarbazine; Time Factors
PubMed: 10521668
DOI: 10.1016/s1383-5718(99)00060-1 -
Journal of Molecular Recognition : JMR May 2017Interaction of procarbazine (PCZ) with calf thymus DNA was studied using biophysical and molecular docking studies. Procarbazine was to interact with DNA with a binding...
Interaction of procarbazine (PCZ) with calf thymus DNA was studied using biophysical and molecular docking studies. Procarbazine was to interact with DNA with a binding constant of 6.52 × 10 M as calculated using ultraviolet-visible spectroscopy. To find out the binding mode, molecular docking was performed that predicted PCZ to interact with DNA through groove binding mode with binding affinity of -6.7 kcal/mole. To confirm the groove binding nature, different experiments were performed. Dye displacement assays confirmed the non-intercalative binding mode. Procarbazine displaced Hoechst dye from the minor groove of DNA while it was unable to displace intercalating dyes. There was no increase in the viscosity of DNA solution in presence of PCZ. Also, negligible change in the secondary structure of DNA was observed in presence of PCZ as evident by circular dichroism spectra. Procarbazine caused decrease in the melting temperature of DNA possibly because of decrease in the stability of DNA caused by groove binding interaction of PCZ with DNA.
Topics: Animals; Binding Sites; Cattle; Circular Dichroism; DNA; Models, Molecular; Molecular Docking Simulation; Procarbazine; Temperature; Viscosity
PubMed: 27917540
DOI: 10.1002/jmr.2599 -
Mutation Research Feb 1979Procarbazine is used in drug-combination treatment of Hodgkin's disease. The specific locus method was used to test and confirm the ability of procarbazine to induce...
Procarbazine is used in drug-combination treatment of Hodgkin's disease. The specific locus method was used to test and confirm the ability of procarbazine to induce gene mutations in pre- and post-meiotic germ cells of male mice. The lowest dose of procarbazine that significantly increased the mutation frequency in As spermatogonia over the control frequency was 400 mg/kg (P = 0.003). The corresponding dose for the post-spermatogonial germ-cell stages was 600 mg/kg (P = 0.009). The dose--response was linear for the point estimates of the mutation frequencies after treatment of As spermatogonia with 0, 200, 400 and 600 mg/kg. The point estimate of the mutation frequency at the 800 mg/kg level was one-third of that expected from a linear extrapolation. Variation in mutation rates among the 7 loci between the lowest (a locus) and the highest (p locus) was 12-fold. Only 24% of procarbazine-induced specific locus mutations in As spermatogonia were lethal in the homozygous condition. From the mutation spectra and the viability tests, it is concluded that procarbazine-induced mutations may be mainly due to base-pair changes. Procarbazine-induced specific-locus mutations fulfilled the criteria for the estimation of the doubling dose, the dose necessary to induce as many mutations as occur spontaneously. The doubling dose of procarbazine in As spermatogonia of mice was 114 mg/kg. The therapeutic dose for procarbazine is about 215 mg/kg. If man and mouse were equally sensitive, this dose would induce 1.9 times as many mutations as arise spontaneously. From the incidence of patients with Hodgkin's disease (1 : 42 000) the calculated population dose of procarbazine is 5.12 micrograms/kg. Assuming equal sensitivity between the sexes we can calculate, for an estimated number of 30 000 genes, the induction of about 22 mutations per million children due to procarbazine treatment. The same number of induced mutations can be calculated if the risk of patients is used for the estimation of the genetic hazard.
Topics: Animals; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Gene Frequency; Genes; Male; Mice; Mutagens; Mutation; Procarbazine; Spermatogonia; Spermatozoa
PubMed: 440322
DOI: 10.1016/0027-5107(79)90163-5 -
Journal of Clinical Oncology : Official... Aug 2010Vincristine, etoposide, prednisone, and doxorubicin (OEPA)-cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDAC) is derived from standard vincristine,...
PURPOSE
Vincristine, etoposide, prednisone, and doxorubicin (OEPA)-cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDAC) is derived from standard vincristine, procarbazine, prednisone, and doxorubicin (OPPA)-cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) chemotherapy by replacing procarbazine with etoposide and dacarbazine for a potentially less gonadotoxic regimen for boys with Hodgkin's lymphoma (HL).
PATIENTS AND METHODS
Five hundred seventy-three pediatric patients with classical HL were enrolled onto the German Society of Pediatric Oncology and Hematology-Hodgkin's Disease (GPOH-HD) -2002 study between November 2002 and December 2005. Boys received two courses of OEPA and girls received two courses of OPPA for induction. Treatment group (TG) -2 (intermediate stages) and TG-3 (advanced stages) patients received further two or four cycles COPP (girls) or COPDAC (boys), respectively. After chemotherapy all patients received involved-field irradiation with 19.8 Gy, except for patients with early-stage disease (TG-1) in complete remission.
RESULTS
Five hundred seventy-three patients (287 males and 286 females) were less than 18 years old and fulfilled all inclusion criteria; 195 patients (34.0%) were allocated to TG-1, 139 (24.3%) were allocated to TG-2, and 239 (41.7%) were allocated to TG-3. Toxicity of OEPA-COPDAC was tolerable overall. Hematotoxicity was more pronounced with OEPA than OPPA, whereas it was less pronounced with COPDAC compared with COPP. The median observation time was 58.6 months. Overall survival and event-free survival (EFS) rates (+/- SE) at 5 years were 97.4% +/- 0.7% and 89.0% +/- 1.4%, respectively. In TG-1, overall EFS was 92.0% +/- 2.0%. EFS of patients without irradiation (93.2% +/- 3.3%) was similar to that of irradiated patients (91.7% +/- 2.5%), confirming results of the previous GPOH-HD-95 study. In TG-2+3, EFS did not significantly differ between boys and girls (90.2% +/- 2.3 v 84.7% +/- 2.7, respectively; P = .12).
CONCLUSION
In TG-2+3, results in boys and girls are superimposable. OPPA-COPP and OEPA-COPDAC seem to be exchangeable regimens in intermediate- and advanced-stage classical HL in pediatric patients.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Dacarbazine; Doxorubicin; Etoposide; Female; Hodgkin Disease; Humans; Male; Prednisone; Procarbazine; Treatment Outcome; Vincristine
PubMed: 20625128
DOI: 10.1200/JCO.2009.26.9381