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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 -
Archives of Biochemistry and Biophysics Mar 1983The oxidative metabolism of procarbazine, its azo, hydrazone, and two azoxy derivatives, and methylhydrazine by hepatic microsomes from phenobarbital-pretreated rats was...
The oxidative metabolism of procarbazine, its azo, hydrazone, and two azoxy derivatives, and methylhydrazine by hepatic microsomes from phenobarbital-pretreated rats was investigated to elucidate the pathway of metabolism that resulted in methane formation from procarbazine. When incubated with microsomal reaction mixtures fortified with NADPH, all of the compounds, except the azoxy isomers, were metabolized to yield methane. A lag phase in methane formation was noted for procarbazine, but not for the other compounds. Kinetic and inhibition studies utilizing methimazole and ethylhydrazine precluded methylhydrazine as an intermediate in methane formation from procarbazine. When the azo derivative was oxidatively metabolized in the presence of liver microsomes, no hydrazone tautomer was detected. Upon monitoring the production of the azo and hydrazone metabolites formed during microsomal metabolism of procarbazine, the azo derivative was formed in sufficient quantities to account for the majority of the methane produced. In addition, small amounts of hydrazone were also detected. It was concluded that both the azo and hydrazone metabolites of procarbazine contribute to methane formation from the terminal methyl group of the hydrazine with the azo derivative being the predominant source and the hydrazone derivative being a minor source of methane. Consideration of the chemical and enzymatic pathways of procarbazine oxidation and the implication of a methyl radical intermediate in methane formation are discussed.
Topics: Animals; In Vitro Techniques; Male; Methane; Microsomes, Liver; Procarbazine; Rats; Rats, Inbred Strains
PubMed: 6838211
DOI: 10.1016/0003-9861(83)90178-9 -
Veterinary and Comparative Oncology Sep 2018The standard of care treatment for canine lymphoma is multi-agent chemotherapy containing prednisolone, cyclophosphamide, vincristine and an anthracycline such as...
Evaluation of a multi-agent chemotherapy protocol combining lomustine, procarbazine and prednisolone (LPP) for the treatment of relapsed canine non-Hodgkin high-grade lymphomas.
The standard of care treatment for canine lymphoma is multi-agent chemotherapy containing prednisolone, cyclophosphamide, vincristine and an anthracycline such as doxorubicin (CHOP) or epirubicin (CEOP). Lomustine, vincristine, procarbazine, and prednisone (LOPP) has been evaluated as a rescue, with encouraging results; however, resistance to vincristine is likely in patients relapsing on CHOP/CEOP, and this agent may enhance LOPP toxicity without improving efficacy. The aim of this study was to evaluate responses to a modified-LOPP protocol that does not include vincristine (LPP) and is administered on a 21-day cycle. Medical records of dogs with high-grade multicentric lymphoma from 2012 to 2017 were reviewed. Dogs with relapsed lymphoma that received LPP as a rescue protocol were enrolled. Response, time from initiation to discontinuation (TTD) and toxicity of LPP were assessed. Forty-one dogs were included. Twenty-five dogs (61%) responded to LPP including 12 complete responses (CR) and 13 partial responses (PR). Responders had a significantly longer TTD (P < .001) compared to non-responders with 84 days for CR and 58 days for PR. Neutropenia was documented in 20 dogs (57%): 12 grade I to II, 8 grade III to IV. Thrombocytopenia was infrequent (20%): 5 grade I to II, 2 grade III to IV. Twelve dogs developed gastrointestinal toxicity (30%): 10 grade I to II and 2 grade III. Nineteen dogs had elevated ALT (59%): 9 grade I to II, 10 grade III to IV. Treatment was discontinued due to toxicity in 8 dogs (19%). The LPP protocol shows acceptable efficacy and toxicity-profile and minimizes in-hospital procedures.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dog Diseases; Dogs; Female; Lomustine; Lymphoma, Non-Hodgkin; Male; Neutropenia; Prednisolone; Procarbazine; Recurrence; Treatment Outcome
PubMed: 29380942
DOI: 10.1111/vco.12387 -
Mutation Research Jan 1991Procarbazine (Natulan) was tested for its mutagenic potency and specificity in the ad-3 forward-mutation test in heterokaryon 12 (H-12) of Neurospora crassa. In these... (Comparative Study)
Comparative Study
Procarbazine (Natulan) was tested for its mutagenic potency and specificity in the ad-3 forward-mutation test in heterokaryon 12 (H-12) of Neurospora crassa. In these experiments, procarbazine was a weak mutagen when present in growing cultures but nonmutagenic when conidial suspensions (nongrowing conidia) were treated. A total of 208 ad-3 mutants recovered after exposure of growing cultures of H-12 to 1 mg of procarbazine/ml, and 2 ad-3 mutants of spontaneous origin, were characterized genetically. These tests distinguish among gene/point mutations (ad-3R) at the ad-3A or ad-3B locus, multilocus deletion mutations ([ad-3]IR) covering one or more loci in the ad-3 and immediately adjacent regions, and 3 different classes of multiple-locus mutations: gene/point ad-3 mutations with a recessive lethal mutation elsewhere in the genome (ad-3R + RL), gene/point mutations with a closely linked recessive lethal mutation (ad-3R + RLCL), and multilocus deletion mutations with a closely linked recessive lethal mutation ([ad-3]IR + RLCL). All of the procarbazine-induced ad-3 mutants resulted from gene/point mutations; 92.2% (200/217) resulted from gene/point mutations at the ad-3A or ad-3B locus, and 3.7% (8/217) resulted from gene/point mutations with a recessive lethal mutation elsewhere in the genome. Identical percentages (15.4% [20/130] and 15.4% [12/78]) of the sigma ad-3BR and sigma ad-3AR mutants were leaky, and a high percentage (71.5% [93/130]) of the sigma ad-3BR mutants had nonpolarized complementation patterns. These results indicate that procarbazine-induced ad-3 mutants of Neurospora crassa are composed solely of gene/point mutations (ad-3R) that resulted, predominantly or exclusively, from base-pair substitutions. The Neurospora specific-locus data on procarbazine-induced ad-3 mutants are compared with data from similar experiments with the mouse using the morphological specific-locus assay; marked similarities were found between the mutagenic effects of procarbazine in the 2 specific-locus assays.
Topics: Alleles; Dose-Response Relationship, Drug; Mutagenicity Tests; Mutation; Neurospora crassa; Procarbazine
PubMed: 1824718
DOI: 10.1016/0027-5107(91)90122-5 -
Biochemical Pharmacology Sep 1984The metabolism of procarbazine was studied using spin-trapping techniques. The oxidation of procarbazine, catalyzed by horseradish peroxidase, prostaglandin synthetase...
The metabolism of procarbazine was studied using spin-trapping techniques. The oxidation of procarbazine, catalyzed by horseradish peroxidase, prostaglandin synthetase [ram seminal vesicle (RSV) microsomes] or rat hepatic microsomal cytochrome P-450, produced carbon-centered free radicals. Cytochrome P-450 also catalyzed this oxidation in the presence of hydrogen peroxide. Horseradish peroxidase activation of procarbazine formed both the methyl radical and the N-isopropylbenzylamide radical [(CH3)2CHNHCO(C6H4)CH2.]. In the presence of RSV or rat hepatic microsomes, mostly the benzyl-type radical was trapped, presumably due to the reactivity of the methyl radical.
Topics: Animals; Biotransformation; Cyclic N-Oxides; Free Radicals; Horseradish Peroxidase; In Vitro Techniques; Male; Microsomes, Liver; Procarbazine; Prostaglandin-Endoperoxide Synthases; Rats; Seminal Vesicles; Sheep; Spin Labels
PubMed: 6431996
DOI: 10.1016/0006-2952(84)90695-6 -
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 -
Tissue & Cell 1983Procarbazine, an anti-cancer agent, administered intraperitoneally to adult, male rats induced a characteristic morphological pattern of response in the seminiferous...
Morphological pattern of response after administration of procarbazine: alteration of specific cell associations during the cycle of the seminiferous epithelium of the rat.
Procarbazine, an anti-cancer agent, administered intraperitoneally to adult, male rats induced a characteristic morphological pattern of response in the seminiferous epithelium. Seminiferous tubules of rats receiving 100 mg/kg procarbazine and higher dosages displayed spermatids which were less mature than those normally found within seminiferous tubules which show a particular cell association. Early spermatids in steps 1-7 of spermiogenesis appeared arrested in their development and were present in cell associations which had advanced normally. The most probable cause of this apparent germ cell arrest was a retardation of acrosomal development since procarbazine is known to affect RNA and consequently protein synthesis. Other features which indicated defective RNA synthesis were the presence of abnormal spermatid nucleoli and abnormally configured chromatoid bodies. This study demonstrates, in contrast to what is indicated by present dogma, that apparent and temporary germ cell arrest may occur under certain deleterious conditions. It also illustrates that particular cell types within a cell association may be out of synchrony with the remainder of the cells in a cell association.
Topics: Animals; Dose-Response Relationship, Drug; Epithelium; Intercellular Junctions; Male; Microscopy, Electron; Procarbazine; Rats; Seminiferous Tubules; Spermatids; Spermatogenesis; Testis
PubMed: 6612709
DOI: 10.1016/0040-8166(83)90071-x -
Cancer Research May 1990O6-Methylguanine was measured by a competitive repair assay in blood leukocyte DNA of seven patients with Hodgkin's or non-Hodgkin's lymphoma during therapeutic exposure...
O6-Methylguanine was measured by a competitive repair assay in blood leukocyte DNA of seven patients with Hodgkin's or non-Hodgkin's lymphoma during therapeutic exposure to procarbazine involving three daily p.o. doses (50 mg each) for 10 days (corresponding to 2.1 mg/kg/day for a 70-kg human). Adduct accumulation was observed in all seven cases, reaching levels up to 0.28 fmol/microgram of DNA (0.45 mumol/mol of guanine). In one individual, maximal levels of adduct were reached after 7 days of exposure, followed by a steady decline, whereas in all other individuals continuous accumulation was observed throughout the exposure period. In four individuals for which data were available for Day 11 (12 to 16 h after the final intake of procarbazine), decreased amounts of O6-methylguanine were observed relative to the last previous measurements. The accumulation of O6-methylguanine was linearly correlated (P less than 0.01) with the cumulative dose of procarbazine, with a slope of 0.011 fmol of O6-methylguanine/microgram of DNA per mg/kg of body weight or 2.68 x 10(-4) fmol of O6 methylguanine DNA per mg/m2. (Two h after the administration of single p.o. doses of 1 to 10 mg/kg of procarbazine to rats, O6-methylguanine formation in leukocyte DNA was just under half that in liver DNA and showed a linear relationship with dose with a slope of 0.017 fmol/microgram of DNA per mg/kg of body weight or 5.67 x 10(-4) fmol of O6-methylguanine/microgram of DNA per mg/m2. A negative correlation (P less than 0.05) between the rate of accumulation of O6-methylguanine in different individuals and lymphocyte O6-alkylguanine-DNA alkyltransferase (AGT) was observed, demonstrating a probable protective effect of AGT against the accumulation of O6-methylguanine during exposure to methylating agents. This observation supports the suggestion of a possible role of procarbazine-induced O6-methylguanine in the pathogenesis of acute nonlymphocytic leukemia appearing after treatment with chemotherapeutic protocols which include procarbazine, based on the finding of low lymphocyte AGT levels in patients with such therapy-related neoplastic disease (Sagher et al., Cancer Res., 48: 3084-3089, 1988). Lymphocyte AGT levels were mainly in the range of 5 to 10 fmol/micrograms of DNA and showed no consistent variation during procarbazine exposure.
Topics: Adult; Aged; DNA; DNA Repair; Dose-Response Relationship, Drug; Guanine; Humans; Leukocytes; Liver; Male; Methyltransferases; Middle Aged; O(6)-Methylguanine-DNA Methyltransferase; Procarbazine
PubMed: 2328502
DOI: No ID Found -
Clinical Pharmacology and Therapeutics Aug 1997Procarbazine usage in brain tumors has a high incidence of hypersensitivity reactions compared with its use in other malignancies. Procarbazine oxidation to a reactive...
BACKGROUND
Procarbazine usage in brain tumors has a high incidence of hypersensitivity reactions compared with its use in other malignancies. Procarbazine oxidation to a reactive intermediate is enhanced by phenobarbital. Patients with primary brain tumors would have a preferential exposure to anticonvulsants compared to patients with other malignancies.
OBJECTIVE
To determine whether anticonvulsant exposure is associated with procarbazine hypersensitivity reactions in patients with primary brain tumors.
METHODS
This retrospective cohort study included 83 patients with primary brain tumors who were treated with procarbazine between 1981 and 1996 at a university hospital-based regional oncology center. Data were extracted by chart review. The data collected included age, sex, race, tumor type, smoking, alcohol usage, and all concomitant medications, as well as creatinine, aspartate aminotransferase, total bilirubin, and anticonvulsant serum levels. Anticonvulsant exposure was determined by the presence of detectable serum levels. Cases of procarbazine hypersensitivity reactions were identified through a review of progress notes.
RESULTS
There were 20 patients with procarbazine hypersensitivity reactions. A significant association between the exposure to anticonvulsants and the development of procarbazine hypersensitivity reactions was found (p = 0.05). In addition, there was a significant dose-response association between the development of procarbazine hypersensitivity and the presence of therapeutic anticonvulsant serum levels (p = 0.03).
CONCLUSIONS
Concomitant exposure to anticonvulsants is associated with procarbazine hypersensitivity reactions, possibly though a reactive intermediate generated by CYP3A isoform induction. All patients in this cohort received enzyme-inducing anticonvulsants. New anticonvulsants devoid of this property are available. These data support trials that use these newer agents for the prophylaxis of seizures in patients with brain tumors who are to receive procarbazine.
Topics: Adult; Anticonvulsants; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carbamazepine; Cohort Studies; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Phenobarbital; Phenytoin; Procarbazine; Retrospective Studies; Valproic Acid
PubMed: 9284859
DOI: 10.1016/S0009-9236(97)90071-0 -
Journal of the American Veterinary... Jul 2011To evaluate the toxicity and efficacy of a modification of a previously evaluated combination of lomustine, vincristine, procarbazine, and prednisone (LOPP) as a rescue...
Evaluation of the University of Florida lomustine, vincristine, procarbazine, and prednisone chemotherapy protocol for the treatment of relapsed lymphoma in dogs: 33 cases (2003-2009).
OBJECTIVE
To evaluate the toxicity and efficacy of a modification of a previously evaluated combination of lomustine, vincristine, procarbazine, and prednisone (LOPP) as a rescue protocol for refractory lymphoma in dogs.
DESIGN
Retrospective case series. Animals-33 dogs with a cytologic or histologic diagnosis of lymphoma that developed resistance to their induction chemotherapy protocol.
PROCEDURES
Lomustine was administered on day 0 of the protocol. Vincristine was administered on day 0 and again 1 time on day 14. Procarbazine and prednisone were administered on days 0 through 13 of the protocol. This cycle was repeated every 28 days.
RESULTS
Median time from initiation to discontinuation of the University of Florida LOPP protocol was 84 days (range, 10 to 308 days). Overall median survival time was 290 days (range, 51 to 762 days). Overall response rate with this protocol was 61% (20/33), with 36% (12) having a complete response and 24% (8) having a partial response. Toxicosis rates were lower than for the previously published LOPP protocol.
CONCLUSIONS AND CLINICAL RELEVANCE
The University of Florida LOPP protocol may be an acceptable alternative to the mechlorethamine, vincristine, procarbazine, and prednisone protocol as a rescue protocol for dogs with lymphoma.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dog Diseases; Dogs; Drug Resistance, Neoplasm; Lomustine; Lymphoma; Prednisone; Procarbazine; Recurrence; Retrospective Studies; Vincristine
PubMed: 21756176
DOI: 10.2460/javma.239.2.209