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Bioorganic Chemistry Mar 2019Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or β position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5-steps process. The...
Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or β position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5-steps process. The overall yield was 32.7%. The new entity Z-GP-Pcb was confirmed targeting to fibroblast activation protein-α (FAPα). Z-GP-Pcb may be hydrolyzed by either isolated rhFAPα or tumor homogenate. It was shown far less cytotoxicity against NCI-H460 cell line than Pcb. Z-GP-Pcb was displayed the potency to reduce spermatoxcity in H22-bearing mice. The mechanism may be ascribed to the blockade of dehydrogenation by α-glycerolphosphate dehydrogenase. This candidate was further proved equal antitumor activity to Pcb. However, the introduction of Z-GP scaffold decreased myelosuppression. All the evidences support that Z-GP-Pcb is a better antitumor agent than Pcb.
Topics: Animals; Antineoplastic Agents; Blood Cell Count; Blood Cells; Blood Platelets; Cell Line, Tumor; Dipeptides; Drug Design; Endopeptidases; Erythrocytes; Gelatinases; Humans; Hydrolysis; Leukocytes; Male; Membrane Proteins; Mice; Organ Size; Procarbazine; Prodrugs; Serine Endopeptidases; Sperm Count; Spermatozoa; Testis
PubMed: 30448724
DOI: 10.1016/j.bioorg.2018.11.011 -
Carcinogenesis Sep 1990Procarbazine hydrochloride (PCZ), a chemotherapeutic agent used extensively to treat Hodgkins disease and other tumors, induces leukemia, lymphoma, mammary gland and...
Procarbazine hydrochloride (PCZ), a chemotherapeutic agent used extensively to treat Hodgkins disease and other tumors, induces leukemia, lymphoma, mammary gland and other solid tumors in rodents and non-human primates and is strongly implicated as a leukemogen in humans. Lipotrope (choline and methionine) deficiency is a powerful potentiator of chemical carcinogenesis in liver and, under some conditions, in other tissues in rodents. Methotrexate (MTX), another commonly used chemotherapeutic agent, interferes with one-carbon metabolism and limits availability of lipotropes. Studies of PCZ carcinogenesis in lipotrope-deficient or MTX-treated male rats are reported, showing that both deficiency and MTX increased PCZ carcinogenicity in the mammary gland. In addition, PCZ was found to induce abnormalities of hepatic choline metabolism. Weanling male Sprague-Dawley rats were fed control (C) or lipotrope-deficient (D) diet. After 3 weeks, C and D rats were given PCZ, MTX, the two drugs together or 0.9% saline by i.p. injection. Doses were 0.2 or 0.5 mg MTX/kg or 25 mg PCZ/kg, given 2 or 3 days per week for 5 or 14 weeks. After 5 weeks of drug treatment livers were assayed for choline, phosphatidylcholine, phosphocholine (PCho), glycerophosphocholine and betaine. PCZ perturbed choline metabolism, increasing hepatic choline and PCho in deficient or MTX-treated rats and, to a smaller extent, in rats fed control diet. MTX markedly enhanced the effect of PCZ on choline metabolism. PCZ-induced mammary tumor incidence was increased 50-70% by lipotrope deficiency or by MTX. In PCZ-treated rats, cumulative probability of bearing a mammary tumor was significantly increased by lipotrope deficiency (P = 0.05), and was increased similarly but not significantly by MTX (P = 0.1). Cumulative tumor numbers per group in PCZ-treated rats were significantly greater in both deficient and MTX-treated rats compared to rats fed control diet (P less than 0.005). Incidences of leukemia, lymphoma and Zymbal's gland tumors induced by PCZ were not significantly altered by diet or MTX.
Topics: Animals; Carcinogens; Choline Deficiency; Leukemia, Experimental; Lipid Metabolism; Liver; Male; Mammary Neoplasms, Experimental; Methotrexate; Neoplasms, Experimental; Procarbazine; Rats; Rats, Inbred Strains; Reference Values
PubMed: 2401040
DOI: 10.1093/carcin/11.9.1491 -
Reevaluation of procarbazine for the treatment of recurrent malignant central nervous system tumors.Cancer Dec 1989Ninety-nine patients with primary recurrent malignant tumors of the central nervous system were treated with procarbazine as a single agent. Procarbazine was not given... (Review)
Review
Ninety-nine patients with primary recurrent malignant tumors of the central nervous system were treated with procarbazine as a single agent. Procarbazine was not given as a specified protocol, but for patients who were ineligible or refused other protocols. All patients had been treated previously with radiotherapy and 96 patients had also received previous chemotherapy. Twenty-five patients were treated at the first progression of their tumor, 47 were treated at the second progression, and 27 were treated at the third progression of their tumor. For the aggregate, the response plus stabilization rate was 27% for glioblastoma multiforme with median time to tumor progression of 30 weeks, and 28% for other anaplastic gliomas with a median time to tumor progression of 49 weeks. With respect to the percent of patients who responded or stabilized to treatment, these results are inferior to those reported previously for patients treated with procarbazine at recurrence. With respect to duration of response and stabilization, the data are comparable.
Topics: Adolescent; Adult; Aged; Brain Neoplasms; Child; Child, Preschool; Female; Glioblastoma; Glioma; Humans; Infant; Male; Middle Aged; Neoplasm Recurrence, Local; Procarbazine; Retrospective Studies; Spinal Cord Neoplasms
PubMed: 2555038
DOI: 10.1002/1097-0142(19891215)64:12<2420::aid-cncr2820641204>3.0.co;2-b -
Mutation Research 1978
Review
Topics: Animals; Carcinogens; Carcinoma, Ehrlich Tumor; Cell Line; Chromosomes, Human; Drosophila melanogaster; Escherichia coli; Female; Humans; Male; Mice; Mutagens; Oogenesis; Pregnancy; Procarbazine; Rats; Spermatogenesis; Teratogens
PubMed: 105288
DOI: 10.1016/0165-1110(78)90009-x -
Current Medicinal Chemistry 2008The methylhydrazine derivative Procarbazine (PCZ) as monotherapy or in combination with CCNU and vincristine (PCV) was evaluated in a vast number of clinical trials and... (Review)
Review
The methylhydrazine derivative Procarbazine (PCZ) as monotherapy or in combination with CCNU and vincristine (PCV) was evaluated in a vast number of clinical trials and is still used in patients with high-grade and low-grade gliomas. The compound is an antineoplastic agent with multiple sites of action. It inhibits incorporation of small DNA precursors, as well as RNA and protein synthesis. PCZ can also directly damage DNA through an alkylation reaction. The drug is not cross-resistant with other mustard-type alkylating agents. As PCZ was in almost all trials used in a combination with CCNU and Vincristin, the efficacy can only be evaluated in the view of the PCV regimen. The published data suggest a role of PCV as a salvage regimen, especially in oligodendroglial tumors; however, well designed studies with high evidence are rare in all entities. This article summarizes the existing data with the goal to define the role of PCZ/PCV in modern neurooncology.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Clinical Trials as Topic; Drug Interactions; Glioma; Humans; Lomustine; Procarbazine; Vincristine
PubMed: 18537615
DOI: 10.2174/092986708784567707 -
Transplantation Jan 1972
Topics: Administration, Oral; Animals; Benzoates; Diarrhea; Dogs; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Procarbazine; Thrombocytopenia; Tissue Survival; Transplantation, Homologous; Vomiting
PubMed: 4550346
DOI: 10.1097/00007890-197201000-00010 -
American Journal of Hospital Pharmacy Nov 1987Reductive destruction of dacarbazine, procarbazine hydrochloride, isoniazid, and iproniazid using nickel-aluminum alloy in basic solution is described. Solutions of...
Reductive destruction of dacarbazine, procarbazine hydrochloride, isoniazid, and iproniazid using nickel-aluminum alloy in basic solution is described. Solutions of dacarbazine 10 mg/mL were prepared by adding dacarbazine 100 mg, citric acid 100 mg, and mannitol 50 mg to 10 mL of water. Aqueous solutions of procarbazine hydrochloride 10 mg/mL were prepared from commercially available capsules, and aqueous solutions of isoniazid 10 mg/mL and iproniazid 5 mg/mL were prepared from powdered drug. Reductive destruction of drugs was accomplished by mixing each solution with an equal volume of 1 M potassium hydroxide solution and adding 1 g of nickel-aluminum alloy for each 20 mL of basified solution. The resulting mixtures were stirred for 20 hours (96 hours for iproniazid) and analyzed by high-performance liquid chromatography and gas chromatography for the presence of residual drug and degradation products. Dacarbazine solutions were also subjected to destruction by photolysis and by oxidation using potassium permanganate in sulfuric acid, and the results were compared with those obtained by reductive destruction. All reaction mixtures were tested for mutagenicity in Salmonella strains. All drugs subjected to reductive destruction were completely degraded to the limits of detection of the assay and produced only nonmutagenic reaction mixtures. The only acceptable results for dacarbazine were obtained by the reductive destruction method. Reduction of dacarbazine, procarbazine hydrochloride, isoniazid, and iproniazid with nickel-aluminum alloy in dilute base appears to be a good method for the destruction of these toxic compounds.
Topics: Alloys; Aluminum; Dacarbazine; Iproniazid; Isoniazid; Mutagenicity Tests; Nickel; Oxidation-Reduction; Procarbazine; Waste Products
PubMed: 3687991
DOI: No ID Found -
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 -
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 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