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Environmental and Molecular Mutagenesis Jul 2019Procarbazine hydrochloride (PCH) is a DNA-reactive hematopoietic carcinogen with potent and well-characterized clastogenic activity. However, there is a paucity of in...
Integrated In Vivo Genotoxicity Assessment of Procarbazine Hydrochloride Demonstrates Induction of Pig-a and LacZ Mutations, and Micronuclei, in MutaMouse Hematopoietic Cells.
Procarbazine hydrochloride (PCH) is a DNA-reactive hematopoietic carcinogen with potent and well-characterized clastogenic activity. However, there is a paucity of in vivo mutagenesis data for PCH, and in vitro assays often fail to detect the genotoxic effects of PCH due to the complexity of its metabolic activation. We comprehensively evaluated the in vivo genotoxicity of PCH on hematopoietic cells of male MutaMouse transgenic rodents using a study design that facilitated assessments of micronuclei and Pig-a mutation in circulating erythrocytes, and lacZ mutant frequencies in bone marrow. Mice were orally exposed to PCH (0, 6.25, 12.5, and 25 mg/kg/day) for 28 consecutive days. Blood samples collected 2 days after cessation of treatment exhibited significant dose-related induction of micronuclei in both immature and mature erythrocytes. Bone marrow and blood collected 3 and 70 days after cessation of treatment also showed significantly elevated mutant frequencies in both the lacZ and Pig-a assays even at the lowest dose tested. PCH-induced lacZ and Pig-a (immature and mature erythrocytes) mutant frequencies were highly correlated, with R values ≥0.956, with the exception of lacZ vs. Pig-a mutants in mature erythrocytes at the 70-day time point (R = 0.902). These results show that PCH is genotoxic in vivo and demonstrate that the complex metabolism and resulting genotoxicity of PCH is best evaluated in intact animal models. Our results further support the concept that multiple biomarkers of genotoxicity, especially hematopoietic cell genotoxicity, can be readily combined into one study provided that adequate attention is given to manifestation times. Environ. Mol. Mutagen. 60:505-512, 2019. © 2018 Her Majesty the Queen in Right of Canada.
Topics: Animals; Carcinogens; Cell Nucleus; DNA Damage; Erythrocytes; Hematopoietic Stem Cells; Lac Operon; Male; Mice; Micronucleus Tests; Mutagenesis; Mutagenicity Tests; Mutagens; Mutation; Procarbazine; Reticulocytes
PubMed: 30592561
DOI: 10.1002/em.22271 -
Environmental and Molecular Mutagenesis Jan 2019The utility and sensitivity of the newly developed flow cytometric Pig-a gene mutation assay have become a great concern recently. In this study, we have examined the...
Assessment of the Pig-a, micronucleus, and comet assay endpoints in rats treated by acute or repeated dosing protocols with procarbazine hydrochloride and ethyl carbamate.
The utility and sensitivity of the newly developed flow cytometric Pig-a gene mutation assay have become a great concern recently. In this study, we have examined the feasibility of integrating the Pig-a assay as well as micronucleus and Comet endpoints into acute and subchronic general toxicology studies. Male Sprague-Dawley rats were treated for 3 or 28 consecutive days by oral gavage with procarbazine hydrochloride (PCZ) or ethyl carbamate (EC) up to the maximum tolerated dose. The induction of CD59-negative reticulocytes and erythrocytes, micronucleated reticulocytes in peripheral blood, micronucleated polychromatic erythrocytes in bone marrow, and Comet responses in peripheral blood, liver, kidney, and lung were evaluated at one, two, or more timepoints. Both PCZ and EC produced positive responses at most analyzed timepoints in all tissue types, both with the 3-day and 28-day treatment regimens. Furthermore, comparison of the magnitude of the genotoxicity responses indicated that the micronucleus and Comet endpoints generally produced greater responses with the higher dose, short-term treatments in the 3-day study, while the Pig-a assay responded better to the cumulative effects of the lower dose, but repeated subchronic dosing in the 28-day study. Collectively, these results indicate that integration of several in vivo genotoxicity endpoints into a single routine toxicology study is feasible and that the Pig-a assay may be particularly suitable for integration into subchronic dose studies based on its ability to accumulate the mutations that result from repeated treatments. This characteristic may be especially important for assaying lower doses of relatively weak genotoxicants. Environ. Mol. Mutagen. 60:56-71, 2019. © 2018 Wiley Periodicals, Inc.
Topics: Animals; CD59 Antigens; Comet Assay; Erythrocytes; Glycosylphosphatidylinositols; Male; Micronucleus Tests; Mutagens; Procarbazine; Rats; Rats, Sprague-Dawley; Reticulocytes; Urethane
PubMed: 30240497
DOI: 10.1002/em.22227 -
Mutagenesis Mar 1988
Review
Topics: Animals; Humans; Mutagenicity Tests; Mutagens; Mutation; Procarbazine
PubMed: 3288843
DOI: 10.1093/mutage/3.2.89 -
Psycho-oncology Jan 2014Procarbazine is an anticancer agent that also inhibits monoamine oxidase, an enzyme responsible for the metabolism of various catecholamines, including serotonin.
BACKGROUND
Procarbazine is an anticancer agent that also inhibits monoamine oxidase, an enzyme responsible for the metabolism of various catecholamines, including serotonin.
METHODS
A retrospective chart review of lymphoma patients who were treated with both procarbazine and an antidepressant, as well as procarbazine alone, was performed to determine if signs and symptoms of serotonin toxicity were present.
RESULTS
A total of 65 patients received procarbazine between 2004 and 2010 and were eligible to be included in the study. Twenty-six of these patients received an antidepressant in combination with procarbazine, with selective serotonin reuptake inhibitors being the most common type of antidepressant. No patients in the study were diagnosed with serotonin toxicity, nor did any meet Hunter's diagnostic criteria for serotonin toxicity. Diarrhea, tremor, and shivering were the symptoms from Sternbach's criteria that were further analyzed, with diarrhea occurring 8.54% of the time, tremor occurring 5.53% of the time, and shivering occurring 2.51% of the time in patients who received an antidepressant with their procarbazine. Despite these symptoms, the diagnosis of serotonin toxicity according to Sternbach's criteria was determined to be unlikely.
CONCLUSIONS
In this small sample of patients treated with procarbazine plus an antidepressant (most typically SSRIs), there were no reports of serotonin toxicity, nor did any patients demonstrate symptoms consistent with serotonin toxicity. The authors urge clinicians to ensure depression is adequately managed in cancer patients who are undergoing procarbazine therapy, starting with typical first-line antidepressant agents.
Topics: Antidepressive Agents; Antineoplastic Agents; Drug Interactions; Female; Humans; Lymphoma; Male; Middle Aged; Procarbazine; Retrospective Studies; Serotonin; Selective Serotonin Reuptake Inhibitors
PubMed: 24038727
DOI: 10.1002/pon.3378 -
Journal of Comparative Pathology Nov 1989Procarbazine hydrochloride, and antineoplastic drug, was administered to pregnant rats from days 13 to 16 of gestation at doses of 0, 1, 5 and 15 mg per kg as part of a...
Procarbazine hydrochloride, and antineoplastic drug, was administered to pregnant rats from days 13 to 16 of gestation at doses of 0, 1, 5 and 15 mg per kg as part of a behavioural study. Histological examination of the brains from the offspring at 12 to 15 weeks of age revealed cerebral atrophy, which increased in severity with increasing dose, together with a reduction in neuronal numbers, with no apparent effect upon the astrocyte and oligodendrocyte populations.
Topics: Abnormalities, Drug-Induced; Animals; Astrocytes; Cerebral Cortex; Female; Neurons; Oligodendroglia; Pregnancy; Procarbazine; Rats; Rats, Inbred Strains
PubMed: 2607014
DOI: 10.1016/0021-9975(89)90025-x -
Journal of Neuro-oncology Feb 2007To evaluate the feasibility of 1-(4-amino- 2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) of pre-treated procarbazine for elderly... (Clinical Trial)
Clinical Trial
Feasibility and response to 1-(4-amino-2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride chemotherapy with pre-treated procarbazine for elderly patients with newly diagnosed glioblastoma.
PURPOSE
To evaluate the feasibility of 1-(4-amino- 2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) of pre-treated procarbazine for elderly patients with newly diagnosed glioblastomas.
PATIENTS AND METHODS
From January 2004 to March 2005, 7 patients with glioblastoma were enrolled. After maximal surgical resection, patients were treated with two to four cycles of procarbazine (100 mg/m(2) for day 1 to 5), ACNU (80 mg/m(2)/day(1) for day 5), cepharantine (70 mg for day 5 and 12) and vincristine (1.4 mg/m(2) for day 5 and 12).
RESULTS
Significant toxicities of this regimen, including infectious toxicities, are described. Among the 7 patients enrolled, there were 6 patients were died, and one was still alive with disease at 13 months. The 6-month progression-free survival and 1-year overall survival are 29% (95% CI, 16% to 73%) and 29% (95% CI, 16% to 73%), respectively.
CONCLUSION
The chemotherapy regimen is active but too toxic for elderly patients with newly diagnosed glioblastoma.
Topics: Aged; Alkaloids; Antineoplastic Combined Chemotherapy Protocols; Benzylisoquinolines; Brain Neoplasms; Disease-Free Survival; Feasibility Studies; Female; Glioblastoma; Humans; Male; Middle Aged; Neutropenia; Nimustine; Procarbazine; Survival Analysis; Treatment Outcome; Vincristine
PubMed: 16937011
DOI: 10.1007/s11060-006-9223-0 -
AJR. American Journal of Roentgenology Sep 1978
Topics: Humans; Lung Diseases; Male; Middle Aged; Pleural Effusion; Procarbazine; Radiography
PubMed: 99008
DOI: 10.2214/ajr.131.3.527 -
Cancer Chemotherapy and Pharmacology 1983An in vivo assay of the activity of procarbazine, N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride, and several metabolic intermediates against...
The in vivo cytotoxic activity of procarbazine and procarbazine metabolites against L1210 ascites leukemia cells in CDF1 mice and the effects of pretreatment with procarbazine, phenobarbital, diphenylhydantoin, and methylprednisolone upon in vivo procarbazine activity.
An in vivo assay of the activity of procarbazine, N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride, and several metabolic intermediates against IP-implanted L1210 leukemia cells in CDF1 male mice is described. Treatment of tumor-bearing mice with procarbazine at doses of 300-500 mg/kg IP increased the mean lifespan of treated mice by 29%-32% relative to that of untreated animals. Procarbazine treatment with doses of 200-400 mg/kg/day given IP for 3 consecutive days increased mean lifespan by 39%-46%. The major circulating metabolite, azoprocarbazine (N-isopropyl-alpha-(2-methylazo)-p-toluamide), was as active as procarbazine when administered at equivalent doses for 3 consecutive days. A 2:1 mixture of azoxyprocarbazines (N-isopropyl-alpha-(2-methyl-ONN-azoxy)-: and N-isopropyl-alpha-(2-methyl-NNO-azoxy)-p-toluamide) was more active than procarbazine, increasing mean lifespan by 76% using the 3-consecutive-day dose schedule. The effects of pretreatment with procarbazine and drugs that are often co-administered with procarbazine, i.e., phenobarbital, diphenylhydantoin, and methylprednisolone, upon procarbazine anticancer activity against L1210 ascites leukemia cells was also determined. Pretreatment of CDF1 male mice with phenobarbital and diphenylhydantoin for 7 days was found to increase the antineoplastic activity of procarbazine by 13%-24%. Pretreatment with methylprednisolone did not significantly alter procarbazine activity. The effects of pretreatment with procarbazine, which is often administered daily for a period of 2-4 weeks, on procarbazine antineoplastic activity were varied. The results of these preliminary pretreatment studies combined with the finding that procarbazine metabolites have antitumor activity that is equal to or greater than that of the parent drug suggest that current clinical protocols that use procarbazine along with agents capable of altering procarbazine metabolism may involve drug interactions that alter the efficacy of procarbazine as an anticancer agent.
Topics: Animals; Drug Interactions; Leukemia L1210; Male; Methylprednisolone; Mice; Mice, Inbred Strains; Phenobarbital; Phenytoin; Procarbazine
PubMed: 6627598
DOI: 10.1007/BF00254261 -
Environmental and Molecular Mutagenesis May 2013Procarbazine is a genotoxic carcinogen whose DNA-damaging activities are not reliably detected in vitro. We evaluated the in vivo genotoxic effects of procarbazine on...
Procarbazine is a genotoxic carcinogen whose DNA-damaging activities are not reliably detected in vitro. We evaluated the in vivo genotoxic effects of procarbazine on hematopoietic cells of male CD-1 mice using a multi-endpoint study design that scored micronucleated reticulocyte (MN-RET) frequency and gene mutation at the Pig-a locus. CD-1 mice were treated for 3 days with procarbazine, up to 150 mg/kg/day. Blood samples collected on Day 3 exhibited robust induction of MN-RETs, with the high dose group exhibiting a mean 29-fold increase. Blood collected 15 and 30 days after treatment began was analyzed for Pig-a mutation with a dual labeling method that facilitated mutant cell frequency measurements in both total erythrocytes and the reticulocyte subpopulation. Procarbazine significantly increased mutant reticulocyte frequencies by Day 15. Mutant erythrocyte responses were also apparent, with a peak incidence observed for the high dose group on Day 30. These results demonstrate that the complex metabolism and resulting genotoxicity of procarbazine is best evaluated in intact animal models, and show that the flow cytometric methods employed offer a means to efficiently monitor both in vivo chromosomal damage and mutation.
Topics: Animals; Antineoplastic Agents; CD24 Antigen; Chromosomes; DNA Damage; Flow Cytometry; Male; Membrane Proteins; Mice; Micronucleus Tests; Mutagens; Procarbazine; Reticulocytes
PubMed: 23427001
DOI: 10.1002/em.21758 -
Clinical Cancer Research : An Official... Sep 2006Procarbazine hydrochloride (PCB) is one of the few anticancer drugs with activity against high-grade gliomas. This study was conducted to determine if the maximum... (Clinical Trial)
Clinical Trial
PURPOSE
Procarbazine hydrochloride (PCB) is one of the few anticancer drugs with activity against high-grade gliomas. This study was conducted to determine if the maximum tolerated dose and pharmacokinetics of PCB are affected by the concurrent use of enzyme-inducing antiseizure drugs (EIASD).
EXPERIMENTAL DESIGN
Adults with recurrent high-grade glioma were divided into cohorts who were (+) and were not (-) taking EIASDs. PCB was given orally for 5 consecutive days each month. Six patients were evaluated at each dose level beginning with 200 mg/m2/d and escalated using the modified continual reassessment method. Toxicity and response were assessed. Pharmacokinetic studies were done with a new electrospray ionization mass spectrometry assay.
RESULTS
Forty-nine patients were evaluated. The maximum tolerated dose was 393 mg/m2/d for the +EIASD group and the highest dose evaluated in -EIASD patients was 334 mg/m2/d. Myelosuppression was the primary dose-limiting toxicity. Significant hepatic dysfunction occurred in three patients in the +EIASD cohort. Four partial responses (8%) and no complete responses were observed. PCB exhibited linear pharmacokinetics with no significant differences between the two cohorts. A marked increase in peak PCB levels was noted on day 5 relative to day 1, which was not attributable to drug accumulation.
CONCLUSIONS
This study suggests that (a) EIASD use does not significantly affect the pharmacokinetics of PCB; (b) changes in the peak plasma concentration of PCB, consistent with decreased apparent oral clearance due to autoinhibition of hepatic metabolism, occur with daily dosing; and (c) severe hepatic dysfunction may accompany this administration schedule.
Topics: Administration, Oral; Adult; Aged; Anticonvulsants; Antineoplastic Agents; Cohort Studies; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Induction; Female; Follow-Up Studies; Glioma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Procarbazine; Spectrometry, Mass, Electrospray Ionization; Time Factors; Treatment Outcome
PubMed: 16951236
DOI: 10.1158/1078-0432.CCR-06-0932