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Mutagenesis Dec 2017Procarbazine is a primary component of antineoplastic combination chemotherapy often used for the treatment of Hodgkin's lymphoma. It is believed that cytostatic and...
Procarbazine is a primary component of antineoplastic combination chemotherapy often used for the treatment of Hodgkin's lymphoma. It is believed that cytostatic and cytotoxic properties of procarbazine are mediated via its interaction with genomic DNA. Procarbazine is a carcinogen in animal models; it is classified as Group 2A compound by IARC. Also it is known as an in vitro and in vivo mutagen and genotoxicant. However, the molecular mechanism by which procarbazine induces mutations is not thoroughly understood and the spectrum of procarbazine-induced in vivo mutations is described insufficiently. We employed flow cytometry-based erythrocyte and T lymphocyte assays in order to quantify the frequencies of cells deficient in glycosylphosphatidyl inositol-anchored surface markers CD59 and CD48 (presumed mutants in the endogenous X-linked Pig-a gene) in rats. The rats were treated once daily with 100 mg/kg procarbazine HCl for 3 days. In addition, we sorted mutant-phenotype spleen T cells and immediately analysed their Pig-a gene using next generation sequencing of dual-indexed multiplex libraries and error-correcting data filtering. More than 100-fold increase in the frequencies of CD59-deficient RBCs was observed at Day 29 after the last administration, and a 10-fold increase in the frequency of CD48-deficient T cells was observed at Days 45 to 50. Sequencing revealed that, in T cells from procarbazine-treated rats, mutations in the Pig-a gene occurred predominantly at A:T basepairs when A was located on the non-transcribed DNA strand. A→T transversion was the most common mutation. Our results suggest that, at least for the transcribed X-linked Pig-a gene, in vivo methyl guanine adducts are not the major contributors to mutations induced by procarbazine.
Topics: Animals; Antigens, CD; Biomarkers; DNA Mutational Analysis; Membrane Proteins; Mutation; Procarbazine; Rats, Sprague-Dawley; Spleen; T-Lymphocytes
PubMed: 29237063
DOI: 10.1093/mutage/gex032 -
Journal of Chromatography. B,... Jan 2004Procarbazine is a cytotoxic chemotherapeutic agent used in the treatment of lymphomas and brain tumors. Its pharmacokinetic behavior remains poorly understood even...
Procarbazine is a cytotoxic chemotherapeutic agent used in the treatment of lymphomas and brain tumors. Its pharmacokinetic behavior remains poorly understood even though more than 30 years have elapsed since the drug was approved for clinical use. To characterize the pharmacokinetics of procarbazine in brain cancer patients during a phase I trial, a method for determining the drug in human plasma by reversed-phase high-performance liquid chromatography (HPLC) with electrospray ionization mass spectrometry (ESI-MS) was developed and thoroughly validated. Plasma samples were prepared for analysis by precipitating proteins with trichloroacetic acid and washing the protein-free supernatant with methyl tert-butyl ether to remove excess acid. The solution was separated on a Luna C-18 analytical column using methanol-25 mM ammonium acetate buffer, pH 5.1 (22:78, v/v) as the mobile phase at 1.0 ml/min. A single-quadrupole mass spectrometer with an electrospray interface was operated in the selected-ion monitoring mode to detect the [M+H](+) ions at m/z 222.2 for procarbazine and at m/z 192.1 for the internal standard (3-dimethylamino-2-methylpropiophenone). Procarbazine and the internal standard eluted as sharp, symmetrical peaks with retention times (mean+/-S.D.) of 6.3+/-0.1 and 9.9+/-0.3 min, respectively. Calibration curves of procarbazine hydrochloride in human plasma at concentrations ranging from 0.5 to 50 ng/ml exhibited excellent linearity. The mean absolute recovery of the drug from plasma was 102.9+/-1.0%. Using a sample volume of 150 microl, procarbazine was determined at the 0.5 ng/ml (1.9 nM) lower limit of quantitation with a mean accuracy of 105.2% and an interday precision of 3.60% R.S.D. on 11 different days over 5 weeks. During this same time interval, the between-day accuracy for determining quality control solutions of the drug in plasma at concentrations of 2.0, 15 and 40 ng/ml ranged from 97.5 to 98.2% (mean+/-S.D., 97.9+/-0.4%) and the precision was 3.8-6.2% (mean+/-S.D., 5.1+/-1.2%). Stability characteristics of the drug were thoroughly evaluated to establish appropriate conditions to process, store and prepare clinical specimens for chromatographic analysis without inducing significant chemical degradation. The sensitivity achieved with this assay permitted the plasma concentration-time profile of the parent drug to be accurately defined following oral administration of standard doses to brain cancer patients.
Topics: Antineoplastic Agents; Brain Neoplasms; Chromatography, High Pressure Liquid; Clinical Trials, Phase I as Topic; Glioma; Humans; Procarbazine; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization
PubMed: 14670747
DOI: 10.1016/j.jchromb.2003.10.061 -
Journal of Chromatography May 1982Quantitative analytical methods are described for the analysis of the anticancer drug procarbazine and eight known metabolites including those known to have cytotoxic...
Quantitative analytical methods are described for the analysis of the anticancer drug procarbazine and eight known metabolites including those known to have cytotoxic activity. A direct sample insertion mass spectrometric assay for procarbazine and the urinary excretion product, N-isopropyl-terephthalamic acid, has been developed. This method employs stable isotope labeled variants in a procedure that minimizes analytical errors that may be encountered in the quantitation of the chemically unstable parent drug. a liquid chromatographic method is described for the analysis of seven known procarbazine metabolites. Use of these methods is demonstrated by the analysis of procarbazine metabolism during incubation in a 9000-g rat liver homogenate preparation. Procarbazine disappearance and metabolite appearance are also monitored in rat plasma following intraperitoneal administration of a 150 mg/kg bolus dose. Applications to patient pharmacokinetics is demonstrated using the liquid chromatographic assay to follow the appearance of active procarbazine metabolites on the first and fourteenth day of an oral 250 mg/kg/day course of therapy of a patient being treated for cancer.
Topics: Animals; Biotransformation; Chromatography, High Pressure Liquid; Humans; In Vitro Techniques; Liver; Mass Spectrometry; Neoplasms; Procarbazine; Rats; Reference Values
PubMed: 7096474
DOI: 10.1016/s0378-4347(00)84282-6 -
British Journal of Urology Apr 1978Thirty-four men with Peyronie's diseases were treated with a 12-week course of the drug procarbazine (Natulan), preceded or followed by a 12-week course of vitamin E.... (Comparative Study)
Comparative Study
Thirty-four men with Peyronie's diseases were treated with a 12-week course of the drug procarbazine (Natulan), preceded or followed by a 12-week course of vitamin E. Ninety-one per cent of the men failed to improve or became worse whilst receiving Natulan and toxic side-effects were common. In comparison 39% improved whilst taking vitamin E. We concluded that Natulan is of little benefit in the treatment of this condition and may indeed be harmful.
Topics: Adult; Aged; Drug Evaluation; Humans; Male; Middle Aged; Penile Induration; Procarbazine; Vitamin E
PubMed: 754844
DOI: 10.1111/j.1464-410x.1978.tb03038.x -
Toxicology Letters Oct 1981Procarbazine, a non-benzodiazepine tranquilizer and anti-convulsant, significantly decreased the binding of [3H]diazepam to mouse cerebellar membranes. The drug...
Procarbazine, a non-benzodiazepine tranquilizer and anti-convulsant, significantly decreased the binding of [3H]diazepam to mouse cerebellar membranes. The drug treatment reduced both the affinity and density of the receptor. The effect, however, was more pronounced on the number of binding sites suggesting occupation of the receptor by procarbazine. The results suggest that benzodiazepine receptors may also be involved in the pharmacological action of non-benzodiazepine drugs.
Topics: Animals; Binding, Competitive; Brain; Diazepam; Male; Mice; Mice, Inbred DBA; Procarbazine; Receptors, Drug; Receptors, GABA-A; Synapses
PubMed: 6272448
DOI: 10.1016/0378-4274(81)90036-9 -
Cancer Research Mar 1987Procarbazine causes dose-dependent decreases in sperm count after a single i.p. injection in (C57BL/6 X DBA/2)F1 male mice. Two antioxidants, N-acetylcysteine and sodium...
Procarbazine causes dose-dependent decreases in sperm count after a single i.p. injection in (C57BL/6 X DBA/2)F1 male mice. Two antioxidants, N-acetylcysteine and sodium ascorbate, administered with equimolar doses of procarbazine decreased the spermatotoxicity of procarbazine. At the highest doses of procarbazine (400 mg/kg) that caused a 56% decrease in sperm count, equimolar doses of N-acetylcysteine coadministered with procarbazine caused only a 17% decrease in sperm count, and equimolar doses of ascorbate coadministered with procarbazine caused only a 13% decrease in sperm count. Thus, protection against the spermatotoxic effects of procarbazine was demonstrated with either antioxidant. The effect of the antioxidants on the chemotherapeutic efficacy of procarbazine against murine L1210 leukemia was also assessed. Procarbazine at the highest dose (600 mg/kg) increased mean survival time of mice inoculated i.p. with 1 X 10(5) L1210 leukemia cells by 31%. Simultaneous administration of equimolar doses of either N-acetylcysteine or ascorbate given with procarbazine caused no change in the increased mean survival time of tumor-bearing mice. These results indicate a decrease in the toxicity of procarbazine when coadministered with antioxidants, via decreased spermatotoxicity without changing anticancer efficacy. The results also indicate that different mechanisms are involved in the spermatotoxicity and anticancer activity of procarbazine.
Topics: Acetylcysteine; Animals; Ascorbic Acid; Dose-Response Relationship, Drug; Glutathione; Leukemia L1210; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Procarbazine; Spermatozoa
PubMed: 3815355
DOI: No ID Found -
Mutagenesis Mar 1988
Review
Topics: Animals; Humans; Mutagenicity Tests; Mutagens; Mutation; Procarbazine
PubMed: 3288843
DOI: 10.1093/mutage/3.2.89 -
European Journal of Cancer (Oxford,... Sep 2004Procarbazine (PCB) was developed in the 1960s and was rapidly recognised as an active agent in lymphoid malignancies. PCB was one of the four drugs combined in...
Procarbazine (PCB) was developed in the 1960s and was rapidly recognised as an active agent in lymphoid malignancies. PCB was one of the four drugs combined in mechlorethamine, vincristine, PCB, prednisolone (MOPP), one of the first combination chemotherapy regimens to show that advanced-stage disease could be cured in humans. During the last few decades, comprehensive studies have clarified cellular pathways involved in the modes of action of PCB and its drug resistance mechanisms. However, late toxicities, especially secondary leukaemias and sterility, led to its withdrawal from combination regimens used to treat Hodgkin's lymphomas (HLs). PCB was recently reintroduced in dose-intensified regimens and yielded impressive results. These new regimens (bleomycin, etoposide, doxorubicin, vincristine, PCB, and prednisone (BEACOPP) or escalated BEACOPP) are now being investigated versus the classic ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or ABVD-like combination chemotherapy regimens in the treatment of HLs.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Interactions; Drug Resistance, Neoplasm; Hematologic Neoplasms; Humans; Procarbazine; Randomized Controlled Trials as Topic
PubMed: 15315798
DOI: 10.1016/j.ejca.2004.05.015 -
Endocrinology Aug 1995Suppression of spermatogenesis in LBNF1 rats by treatment with the GnRH agonist Zoladex combined with the antiandrogen flutamide was evaluated in order to rapidly...
Suppression of spermatogenesis in LBNF1 rats by treatment with the GnRH agonist Zoladex combined with the antiandrogen flutamide was evaluated in order to rapidly achieve protection of spermatogenic stem cells against procarbazine with clinically used drugs. Zoladex-flutamide treatment required 3 weeks to suppress the completion of spermatogenesis; only a small degree of suppression was observed with Zoladex alone. The suppression of spermatogenesis was reversible. In rats pretreated for 3 weeks with Zoladex-flutamide, the recovery of spermatogenesis at 9 weeks after a single injection of procarbazine as measured by testis weight, testicular sperm head counts, or a histological end point was significantly better than without hormonal pretreatment. Thus Zoladex-flutamide treatment enhanced the recovery of spermatogenesis from stem spermatogonia after procarbazine treatment in the rat and might be applicable to protect spermatogenesis in patients undergoing chemotherapy for cancer.
Topics: Androgen Antagonists; Animals; Drug Combinations; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Hormones; Male; Procarbazine; Rats; Spermatogenesis; Testis
PubMed: 7628410
DOI: 10.1210/endo.136.8.7628410 -
Oncology Research 1992The cellular cytotoxicity of procarbazine is thought to result from bioactivation of the parent compound through reactive intermediates to an ultimate alkylating...
The cellular cytotoxicity of procarbazine is thought to result from bioactivation of the parent compound through reactive intermediates to an ultimate alkylating species. Procarbazine is converted initially to azoprocarbazine, which is then N-oxidized through a cytochrome P-450-mediated process to a mixture of the positional isomers, benzylazoxyprocarbazine and methylazoxyprocarbazine. In order to define the bioactivation events that lead to the cytotoxic species, the in vitro cytotoxicities of the purified azoxy isomers as well as of the parent compound, procarbazine, were evaluated with the human leukemia cell line, CCRF-CEM. The methylazoxy isomer was found to be the most active species. Procarbazine inhibited the growth of CCRF-CEM cells but at a concentration much higher than that required for the methylazoxy isomer. Since procarbazine must be metabolized to form the cytotoxic species, we sought to determine if the active metabolite, methylazoxyprocarbazine, was being formed in the incubations. Solutions of procarbazine incubated with and without cells at 37 degrees C were analyzed by combined liquid chromatography-mass spectrometry with a thermospray interface. The azoxy metabolites of procarbazine appeared rapidly in cellular incubations and in the aqueous solutions without cells. More of the methylazoxy isomer was formed initially, but by 72 hr the benzylazoxy isomer was the predominant species. Thus, in these studies it appears that procarbazine was benzylazoxy isomer was the predominant species. Thus, in these studies it appears that procarbazine was non-enzymatically oxidized to the two azoxyprocarbazine isomers and that the methylazoxy compound was the most cytotoxic to CCRF-CEM cells.
Topics: Biotransformation; Cell Division; Cell Line; Cell Survival; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Humans; Mass Spectrometry; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Procarbazine
PubMed: 1596582
DOI: No ID Found