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Mutation Research 1992The usefulness of the acridine orange (AO) supravital staining technique for the mouse peripheral blood reticulocyte micronucleus test was investigated independently by... (Comparative Study)
Comparative Study
The usefulness of the acridine orange (AO) supravital staining technique for the mouse peripheral blood reticulocyte micronucleus test was investigated independently by three laboratories using the known clastogens procarbazine hydrochloride (PCZ) and mitomycin C (MMC). In all three laboratories the highest frequencies of micronucleated peripheral blood reticulocytes were observed 48 h after treatment of mice with a single dose of either MMC or PCZ. The animals responded to both chemicals in a dose-dependent manner. Although similar qualitative results were observed, mean micronucleus frequencies induced by a particular dose of a given test chemical did vary quantitatively among the three laboratories. This was most probably due to the use of slightly different scoring criteria by each examiner. This aspect needs special attention. To minimize inter-laboratory variability, therefore, we recommend establishing unequivocal criteria to distinguish the subclass of reticulocytes. These should then be used consistently by all investigators using this method. The most striking advantages of the AO supravital staining technique were the ease of slide preparation, the ease with which reticulocytes and mature erythrocytes could be distinguished by the examiners, and the occurrence of numerous scorable reticulocytes in each microscopic field, which greatly speeded up the manual counting process. The disadvantages of the staining technique were the limited scoring time due to the rapid fading of the fluorescence stain, the degradation of the cells with time, and the frequent need to search for adequate scoring areas within a microscopic field. Based on the data of this study the authors conclude that the AO supravital staining technique is highly suitable for the micronucleus assay in erythrocytic cells of mouse peripheral blood. In addition, we consider the mouse peripheral blood reticulocyte micronucleus test to be a useful tool with which to investigate the clastogenic potential of chemicals in vivo. As pretreatment of mice with Aroclor 1254 markedly increased the effect of PCZ on micronucleus induction, we suggest that the inclusion of inducers of drug metabolizing enzymes in the micronucleus test would be useful for the detection of the clastogenic potential of promutagenic chemicals.
Topics: Acridine Orange; Animals; Dose-Response Relationship, Drug; Laboratories; Male; Mice; Mice, Inbred Strains; Micronucleus Tests; Mitomycin; Mutagens; Procarbazine; Reticulocytes
PubMed: 1372706
DOI: 10.1016/0165-1218(92)90234-q -
Scandinavian Journal of Haematology Feb 1980A total of 44 patients with Hodgkin's disease and 23 patients with non-Hodgkin malignant lymphoma were treated with MOPP-combination chemotherapy. 4 patients with...
A total of 44 patients with Hodgkin's disease and 23 patients with non-Hodgkin malignant lymphoma were treated with MOPP-combination chemotherapy. 4 patients with Hodgkin's disease and 8 with non-Hodgkin lymphoma developed urticaria or maculo-papular rash. This frequency of hypersensitivity reactions is higher than that expected from the few cases reported in the literature.
Topics: Drug Hypersensitivity; Hodgkin Disease; Humans; Lymphoma; Procarbazine; Urticaria
PubMed: 7375814
DOI: 10.1111/j.1600-0609.1980.tb02359.x -
Archives of Toxicology Feb 1979A study was carried out on the effects of N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide (procarbazine, Natulan) in the dominant lethal test in the mouse. Male mice...
A study was carried out on the effects of N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide (procarbazine, Natulan) in the dominant lethal test in the mouse. Male mice were dosed once and mated with fresh virgin females each week. The utilization of sperm, treated as spermatids or testicular sperm with 100-800 mg/kg, resulted in significant post- and pre-implantation death of embryos. Fertility was markedly reduced after the injection of 200 mg/kg of procarbazine and over. This is probably due to a cell killing effect, the most sensitive stages being differentiating spermatogonia, type A sermatogonia and resting primary spermatocytes. Total sterility was induced for several weeks with doses of 600 and 800 mg/kg. Up to 12 weeks after treatment the number of females with implants was still significantly lower than controls indicating a severe depletion of spermatogonial cells. The spectrum of effects correlates well with the drug's effect on nucleic acid and protein synthesis.
Topics: Animals; Embryo, Mammalian; Female; Fertility; Genes, Dominant; Genes, Lethal; Germ Cells; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Pregnancy; Procarbazine; Spermatozoa; Time Factors
PubMed: 435078
DOI: 10.1007/BF00296898 -
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 -
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 -
Mutagenesis Sep 1989N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine; 50-1000 micrograms/ml) induced DNA damage in hepatocytes measured by an automated alkaline... (Comparative Study)
Comparative Study
N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine; 50-1000 micrograms/ml) induced DNA damage in hepatocytes measured by an automated alkaline elution method, whereas no significant increase in unscheduled DNA synthesis was seen. In hepatocytes isolated from PCB-treated rats, DNA damage was detected in both test systems at concentrations as low as 1-10 micrograms/ml. DNA damage, as measured by alkaline elution and sister-chromatid exchange(s), was observed also in V79 cells incubated with PCB-hepatocytes. In contrast, no mutagenic activity was observed in the Salmonella typhimurium strain TA1530 co-incubated with the hepatocytes. Exposure of rats to low doses of procarbazine (25-50 mg/kg) caused DNA damage measured by alkaline elution in liver and testis, with the liver being somewhat more sensitive. The genotoxicity caused by procarbazine was increased by a factor of 2-3 in both organs by PCB-treatment of the rats. N-isopropyl-alpha-(2-methyl-hydrazino)-p-[alpha,alpha-2H2]toluamide (d2-procarbazine), was found to cause significantly less genotoxicity in control rats than either procarbazine itself, or N-isopropyl-alpha-(2-[alpha,alpha,alpha-2H3]methylhydrazino)-p-tol uamide (d3-procarbazine). This indicates that benzylic C-H oxidation of procarbazine is an important step in the activation of procarbazine to genotoxic metabolites in uninduced rats.
Topics: Animals; Biotransformation; DNA; DNA Damage; Deuterium; Dose-Response Relationship, Drug; Liver; Male; Mutagenicity Tests; Procarbazine; Rats; Rats, Inbred Strains; Salmonella typhimurium; Sister Chromatid Exchange; Testis
PubMed: 2687629
DOI: 10.1093/mutage/4.5.355 -
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 -
Pharmacology & Therapeutics 1987
Review
Topics: Animals; Antineoplastic Agents; Carcinogens; Humans; Hydrazines; Mutagens; Procarbazine
PubMed: 3310042
DOI: 10.1016/0163-7258(87)90095-7 -
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 -
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