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Biomedical subjects

J A Benvenuto

Publications and source records attributed to J A Benvenuto.

At least 19 recordsLinked to original sources
PubMed1995

Biochemical pharmacology of penclomedine (NSC-338720).

Penclomedine (PEN) is a synthetic pyridine derivative that has been selected for clinical development based on its activity against human and mouse breast tumors implanted in mice. Its mechanism of action was unclear, and we were interested in determining its mechanism of cytotoxicity in vitro and in vivo. We found chromosome breaks, gaps, and exchanges in P388 ascites cells from BD2F1 mice treated with 200 mg/kg PEN. Maximal observed damage occurred 24 hr after drug administration. Alkaline elution indicated only limited DNA strand breaks and interstrand cross-linking. In vitro, PEN (75 micrograms/mL) inhibited RNA and DNA syntheses almost completely. In addition, incubation of [14C]PEN with rat liver S-9 fraction in the presence of calf thymus DNA resulted in the stable transfer of radioactivity to DNA. Addition of butylated hydroxytoluene, a free radical scavenger, to the incubation mixture inhibited the binding of drug to DNA, implicating free radicals as the ultimate reactive species. These data suggest that PEN can be metabolized to free radical, DNA-reactive products, and that its cytotoxicity is due to chromosomal damage produced by monofunctional alkylation. As an alternate mechanism, the ability of PEN to inhibit cellular dihydroorotate dehydrogenase was explored. Although PEN is an inhibitor of this enzyme in cells in vivo, in vitro, and in isolated cell sonicates, HPLC analyses of ribonucleotide triphosphate pools in P388 cells showed that all triphosphates had increased, especially UTP. Addition of uridine to the cell culture failed to prevent PEN-mediated cytotoxicity, suggesting that inhibition of de novo pyrimidine biosynthesis was not likely to be an important mechanism of action of this drug. These data suggest that PEN is activated in cells to a free radical that binds DNA.

Animals↗
PubMed1992

Phase II clinical and pharmacological study of didemnin B in patients with metastatic breast cancer.

Sixteen evaluable patients with metastatic breast cancer were entered into a phase II trial of didemnin B. They received the drug at an initial dose of 5.6 mg/m2 every 21 to 28 days. Major toxicities noted were myalgia and nausea and vomiting while myelosuppression was mild. There were no complete responses; however, two minor responses were observed. The pharmacokinetics of didemnin B were studied in 10 patients who received the drug as 30 to 60 min i.v. infusions. A sensitive competitive inhibition enzyme immunoassay was used to quantitate didemnin B levels. Drug was observed to be rapidly cleared from plasma in a biphasic manner (t1/2 alpha = 0.12 hr, t1/2 beta = 4.8 hr). Although the assay could not identify the presence of specific metabolites, the increase of apparent didemnin B levels in plasma at later time points suggested the formation of unidentified metabolites which cross reacted with the antibody in the analytical procedure. In vitro experiments indicated that didemnin B was not bound to bovine serum albumin and only a minor portion (24%) of drug was found associated with red blood cells.

Adult↗
PubMed1992

Clinical pharmacokinetics of ifosfamide in combination with N-acetylcysteine.

The pharmacokinetics of ifosfamide were studied in 20 patients with soft tissue and bone sarcomas. Drug was administered as a 30-60 min i.v. infusion at 1.2 or 2.0 mg/m2/day for five consecutive days. Some patients also received 1.5 g/m2 of N-acetylcysteine (NAC) administered 3 times per day during the course of therapy. NAC had no effect on ifosfamide pharmacokinetics. There were significant differences in plasma half-life, area under the concentration-time curve and plasma clearance on day 1 versus day 5 of ifosfamide administration. Myelosuppression and granulocytopenia correlated better with day 1 versus day 5 ifosfamide pharmacokinetics suggesting that the alteration of ifosfamide pharmacology with multiple dosing has a significant effect on drug activity.

Acetylcysteine↗
PubMed1991

Phase I clinical investigation of benzisoquinolinedione (amonafide) in adults with refractory or relapsed acute leukemia.

After Phase I studies of benzisoquinolinedione (amonafide) in solid tumors identified myelosuppression as the dose-limiting toxicity, we conducted a Phase I study in patients with relapsed or refractory acute leukemia to define the optimal dose. Amonafide was given i.v. over 2-4 h daily for 5 days. The starting dose was 600 mg/m2/day with subsequent escalation to 750, 900, 1100, 1400, and 1800 mg/m2/day. Thirty-eight courses were administered to 24 patients, of whom 12 participated in concomitant pharmacological studies. Nausea and vomiting, transient orange discoloration of the skin, and tinnitus occurred at all dose levels. The latter symptom, along with lightheadedness and flushing, was related to infusion duration; this was increased to 4 h with doses greater than or equal to 900 mg/m2. The dose-limiting toxicities were mucositis and painful skin erythema which occurred in all 4 patients treated with 1800 mg/m2. No remissions occurred. Clearing of peripheral blood blasts occurred in 67% of patients treated with 1100 mg/m2 and in all patients treated with greater than or equal to 1100 mg/m2/day. A decrease in marrow leukemic infiltrate (% blasts x % cellularity) to less than 10% occurred in 15 and 50% of patients treated at these levels, respectively. There were 10 deaths (42%), which were unrelated to dosage. The harmonic mean terminal plasma half-life was 4.6 h (range, 2.5-35.5 h). Three patients had long drug half-lives of 9.7, 16.4, and 35.5 h and each had initial bilirubin levels greater than 1.0 mg/dl. The average urinary excretion of amonafide over 5 days was 3.5% of the total dose. This establishes 1100-1400 mg/m2/day for 5 days as the maximally tolerated dose of amonafide for studies in acute leukemia.

Acute Disease↗
PubMed1988

The mutagenicity of urine fractions from patients administered antineoplastic therapy.

A concern among hospital personnel is their exposure to mutagenic drugs and in the incidental exposures that could occur in caring for the patients. In a recent published study the mutagenicity of urine from patients administered antineoplastic drugs was determined and techniques were developed to chemically inactivate the mutagenicity. A question still remained as to what components of the excreted urine were mutagenic. Urine samples from patients receiving mutagenic drugs were fractionated by high pressure liquid chromatography (HPLC) to then assay by the Ames test the collected and concentrated fractions to determine what were the mutagenic compounds in the urine. Urine samples from patients on single agent cancer treatment with cisplatin, cyclophosphamide, doxorubicin and mitomycin C were assayed. In general, all urine samples containing the cytotoxic agents studied were mutagenic because of the presence of the parent compound, except cyclophosphamide which requires activation and therefore an active metabolite was the major mutagenic constituent in the urine sample. This data indicates that the mutagenicity of urine from patients receiving these antineoplastic agents is the result of the parent compound or a single major metabolite.

Antineoplastic Agents↗
PubMed1987

Stability and inactivation of mutagenic drugs and their metabolites in the urine of patients administered antineoplastic therapy.

Urine samples from patients administered mutagenic antineoplastic drugs are mutagenic in the Ames assay, and hence may pose a genotoxic hazard to hospital personnel or family members caring for the patient. The urine samples in the present study were tested for mutagenicity in several strains of Salmonella typhimurium that were uvr negative (TA98, TA100) or positive (TA102, UTH8413, UTH8414), and were analyzed for the presence of drugs and their metabolites using high-pressure liquid chromatography (HPLC). Urine samples from cancer patients were kept at room temperature and their mutagenicity as well as the chemical stability of the drugs was tested for a period of 14 days. It was observed that, in general, the urine remained mutagenic for the 14-day period while the parent compound degraded within the first seven days. An exception was cisplatin, which was chemically stable as platinum, but the urine decreased in mutagenicity with time. This decrease was probably the result of ligand exchange with the platinum. Inactivation methods were developed to reduce the genotoxic hazard posed by the mutagenic compounds in the urine. Cisplatin was inactivated by complexing with sodium diethyldithiocarbamate (DDTC). Oxidation of urine containing mitomycin C and doxorubicin (sodium thiosulfate must be added to urine containing doxorubicin) with 5.25% sodium hypochlorite solution (bleach) results in mutagenic inactivation. Urine containing cyclophosphamide and its metabolites was oxidized with alkaline potassium permaganate and the active degradation products trapped with sodium thiosulfate. Both chemical and mutagenic assays are necessary to determine the reduction of risk. Methods of inactivation of mutagenic urine developed in this study are both effective and practical for the reduction of exposure to genotoxic hazards.

Antineoplastic Agents↗
PubMed1986

Phase I study of thymidine (dThd) and cisplatin (DDP) given in combination.

Twenty-three patients with a variety of solid tumors were given thymidine (dThd) at a single dose of 30 g/m2 along with cisplatin (DDP) at escalating doses ranging from 25 to 120 mg/m2. The dThd was administered first, and then after 50% of the total dThd dose had been infused over 1 h, the remaining 50% was given simultaneously with DDP at a separate intravenous site over the next 2 h. Treatment was repeated at 3-week intervals. Gastrointestinal toxicity was dose-limiting and dose-related with increasing dosages of DDP. Central nervous system manifestations occurred in 17% of the patients. Mild myelosuppression was observed only at DDP doses of greater than or equal to 75 mg/m2. Thrombocytopenia was more severe than leukopenia. The maximum tolerated doses on this schedule were 30 g/m2 of dThd and 100 mg/m2 of DDP.

Adult↗
PubMed1985

Sequential administration of thymidine, 5-fluorouracil, and PALA. A phase I-II study.

Twenty-seven patients with colorectal adenocarcinoma, (12) non-small cell bronchogenic carcinoma, (11) gastric adenocarcinoma (3), and adenocarcinoma of unknown primary lesion (1) were treated with the combination of thymidine (TdR), 5-fluorouracil (FU), and N-phosphonacetyl-L-aspartic acid (PALA). PALA 1 g/m2 was given over 1 hour on day 1, followed on day 2 by 30 g of TdR given over 3 hours. FU, 150-300 mg/m2, was administered sequentially over 1 hour immediately following TdR infusion. There were no responses seen using this dose schedule. Gastrointestinal and central nervous system toxicities were dose-limiting. Myelosuppression was seen at all dose levels and was not dose related. Fever and infection occurred in 16% and 3% of the courses. The maximum tolerated dosages on this schedule were PALA, 1 g/m2; TdR, 30 g; and FU, 250 mg/m2. Pharmacologic studies done revealed the following half-lives: TdR, 1.6 hours; thymine, 5.0 hours; FU, 6.8 hours; and FUDR, 3.7 hours. The significant prolongation of the half-life of FU with this drug combination implies that the tumor tissues may be exposed longer to the anticancer action of FU.

Adenocarcinoma↗
PubMed1983

Inhibition of hepatic drug metabolism in the rat after Corynebacterium parvum treatment.

Drug-metabolizing enzyme activities, cytochrome concentration, and protein content of hepatic microsomal preparations from adult, female Sprague-Dawley rats were examined at 1-, 3-, 6-, 10-, 14- and 17-day intervals after administration of a single intravenous injection of Corynebacterium parvum (C. parvum) at a dose of 10 mg/m2. Aniline hydroxylase (AH) activity, aminopyrine demethylase (APD) activity, and cytochrome P-450 concentration were reduced 20-50% on days 3-6 and, thereafter, gradually recovered to control levels by day 17. Cytochrome c reductase activity and cytochrome b5 concentration were reduced significantly (24%) only on day 10. Microsomal protein concentration was unchanged. C. parvum added in vitro had no effect on AH or APD activity. Although livers of treated rats were only slightly (less than 20%) enlarged, gross splenomegaly was apparent, reaching a maximum on day 6. A marked inverse correlation existed between the temporal variation in the size of the spleen and APD activity. In rats killed 6 days after administration of C. parvum at 0.67 to 10.00 mg/m2, a direct relationship was apparent between the adjuvant dose and the magnitude of reduction of APD activity. A similar relationship was apparent between splenomegaly and APD activity. Histopathologic examination of liver sections from treated rats revealed numerous granulomas throughout the parenchyma. The magnitude of enzyme inhibition generally paralleled the severity of the hepatic lesions.

Adjuvants, Immunologic↗
PubMed1983

Human central nervous system pharmacology of pentamethylmelamine and its metabolites.

Pentamethylmelamine (PMM) 80 mg/m2 was administered I.V. to 8 patients during surgical resection of intracerebral tumors. PMM concentrations in tumors were generally much higher than concurrent plasma concentrations, ranging from undetectable (less than .01 micrograms/g) to as high as 4.47 micrograms/g and were much higher in malignant melanoma samples than in astrocytoma samples. PMM was barely detectable or undetectable in most samples of edematous brain tissue adjacent to intracerebral tumor and in temporalis muscle. The PMM metabolites tetramethylmelamine (TeMM), trimethylmelamine (TrMM), and dimethylmelamine (DMM) were each detectable in tumor samples from one or two patients. Monomethylmelamine (MMM) was present in tumor samples from all except one patient. MMM was noted in samples of edematous brain tissue adjacent to tumor from 4 of 8 patients. It was the only PMM metabolite found in brain. TrMM, DMM, and MMM but not PMM, and TeMM were found in tumor cyst fluid from a patient with an intracerebral malignant melanoma. Two patients receiving therapeutic doses of PMM had biopsies taken of subcutaneous malignant melanoma deposits. PMM was undetectable in samples from one patient but reached high concentrations in the other patient. In both patients, MMM was the major metabolite. There was no indication that PMM penetrated into extracerebral tumors more readily than into intracerebral tumors Cerebrospinal fluid (CSF) samples were obtained from one patient without neurological toxicity who received low doses of PMM and from 4 patients receiving high doses of PMM who had developed neurological toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Altretamine↗
PubMed1983

Pharmacological and biochemical interactions of N-(phosphonacetyl)-L-aspartate and 5-fluorouracil in beagles.

N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorouracil (FUra) are both antimetabolites that affect the biosynthetic pathways of pyrimidines. To determine whether these two drugs exhibit synergistic pharmacological or biochemical interactions, we determined the pharmacological and biochemical parameters of PALA and [14C]FUra in 14 beagle dogs which received i.v. bolus administrations of either the single agents or the drug combination. The pharmacokinetic parameters of PALA (four dogs, 20 mg/kg) in plasma, cerebrospinal fluid, and urine were not changed by FUra (10 mg/kg, 30 min after PALA). The pharmacokinetics of [2-(14)C]FUra (six dogs, 10 mg/kg, 20 muCi/kg) was characterized by higher FUra plasma concentrations after pretreatment with PALA (20 mg/kg, 30 min before FUra); this led to a significantly larger area under the drug concentration-time curve, a decreased volume of distribution, and a reduced clearance rate and was associated with higher cerebrospinal fluid concentrations of FUra. The FUra plasma and cerebrospinal fluid half-lives, however, were not significantly altered by PALA. The biochemical determinants of PALA and FUra activity were studied in intestinal mucosa, liver, thymus, spleen, and bone marrow of four dogs. Although the activity of the target enzyme of PALA, L-aspartate carbamoyltransferase, in tissue extracts was decreased at least 50% at 18 to 24 hr after PALA administration (50 mg/kg), the uridine nucleotide pools remained remarkably stable. Intracellular FUra concentrations were not influenced by PALA. The incorporation of 5-fluorouridine triphosphate into RNA was enhanced in intestinal mucosa and liver. In other tissues, however, fluorouridine nucleotide concentrations were not affected by PALA. Free 5-fluorodeoxyuridine monophosphate had the highest concentration in liver and was detectable in all tissues, but it was not altered by PALA treatment. Our results show that the pharmacological and biochemical events after FUra exposure are marginally modulated by PALA in normal dogs. If sensitive tumors with a higher degree of interaction between the two drugs could be identified, limited toxicity to normal tissues can be expected.

Animals↗
PubMed1983

Negative-ion chemical-ionization mass spectrometry of aclarubicin analogs and characterization of two metabolites in man.

Aclarubicin and seven analogs have been characterized by negative-ion chemical-ionization mass spectrometry. The method is highly sensitive (requires 1-10 ng) because of the stable semiquinone radical anions that are produced by resonance electron capture of thermal electrons. Ions in the spectra correspond to the intact molecule (M), M-H2O, aglycone, aglycone-O, and aglycone-2H2O. In addition, ions corresponding to the sequential loss of carbohydrate groups are exhibited in the spectra of compounds with di- and tri-saccharides. Two aclarubicin analogs were isolated from a patient's plasma and were found to be bisanhydroaklavinone, F, and one or both of the epimeric reduction products of the L-cinerulose carbonyl, M1 and N1.

Aclarubicin↗
PubMed1982

Comparison of the reversed-phase high-performance liquid chromatographic separations of fluoropyrimides, pyrimidines, and purines.

The reversed-phase, high-performance liquid chromatographic separation of fluoropyrimidines, pyrimidines, and purines was investigated under isocratic conditions at ambient temperature. The performance of nine analytical, commercially available columns with five mobile phases is compared, and capacity and resolution factors are reported. The variables determining resolution are discussed, and the systems accomplishing the desired separation of fluoropyrimidine and pyrimidine bases and nucleosides are described. The best chromatographic results are achieved by using Spherisorb ODS-2 as stationary phase and 0.05 M monobasic ammonium phosphate (pH 3.5) as mobile phase.

Chromatography, High Pressure Liquid↗
PubMed1982

Pharmacokinetics and metabolism of beta-2'-deoxythioguanosine and 6-thioguanine in man.

Resistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, beta-2'-deoxythioguanosine (beta-TGdR) can overcome TG resistance in animal tumor models and is therefore of potential clinical use. The pharmacokinetics of radiolabeled TG were compared with those of beta-TGdR in patients with cancer after intravenous administration. [35S]-beta-TGdR (5.4 mg/kg, 200 mg/m2, 200 microCi total) was administered to five patients; the radiolabel in the plasma declined with an initial half-life (t1/2) of 14 min and a terminal t1/2 of 19.3 h. Within 24 h, 65% of the radiolabel was excreted in the urine. In contrast, after administration of [35S]-6-TG (3.4 mg/kg, 125 mg/m2, 200 microCi total) the average initial t1/2 was 40 min while the terminal phase t1/2 was 28.9 h. Urinary excretion of the radiolabel was 75% of the dose 24 h after administration. Both thiopurines were rapidly and extensively degraded and excreted as 6-thioxanthine, inorganic sulfate, S-methyl-6-thioxanthine, and 6-thiouric acid in addition to other products. Small amounts of unchanged drug were also excreted. These studies suggest that beta-TGdR is merely a latent form of TG.

Allopurinol↗
PubMed1981

Disposition and metabolism of thiopurines III. beta-2'-Deoxythioguanosine and 6-thioguanine in the dog.

The anticancer agent beta-2' deoxythioguanosine (beta-TGdR, NSC-71261) has potential utility for the treatment of hematologic tumors resistant to 6-thioguanine (TG). We have studied the pharmacology and metabolism of these two agents in the beagle dog. [35S] beta-TGdR was administered as an IV bolus to five dogs at a dose of 10 mg/kg. Plasma radioactivity declined biphasically with an average terminal t 1/2 of 3.7 h. Cumulative urinary excretion of the radiolabel 5 h after administration was 19% of the total dose. In another four dogs that received 100 mg/kg (2.71 g), the average terminal plasma t 1/2 was 7.7 h and the 5-h cumulative urinary excretion was 28% of the total dose. [35S]Thioguanine, 5 mg/kg was similarly administered IV to three beagle dogs. The average terminal t 1/2 of [35S]TG and metabolites was 4.6 h, and the 5-h cumulative urinary excretion of the [35S] label was 47%. Similar studies were conducted in three beagle dogs that received the same dose of [8(14)C]TG. In these studies, however, the terminal phase t 1/2 of 14C in plasma was 1.9 h. Cumulative urinary excretion of the 14C was 40% in 5 h. Both TG and beta-TGdR were rapidly and extensively degraded. Neither of these agents and none of their metabolites was found in the cerebrospinal fluid in significant concentrations. In the dog, beta-TGdR was rapidly metabolized to TG and may serve as a slow release form of TG.

Allopurinol↗
PubMed1981

Pharmacology of pentamethylmelamine in humans.

A rapid, specific high-pressure liquid chromatographic assay was used to study the pharmacology of pentamethylmelamine in 21 patients (28 infusions) receiving 80 to 1500 mg/sq m. In patients with normal liver function, pentamethylmelamine was rapidly cleared from the plasma with a terminal half-life of 2.2 hr. Abnormal liver function tended to correlate with increased half-life and reduced total clearance. In addition, increased neurological toxicity was associated with hepatic abnormalities. The N2,N2,N4,N6-tetramethylmelamine, N2,N4,N6-trimethylmelamine, dimethylmelamine, and monomethylmelamine metabolites were detected in plasma. The terminal plasma half-lives of these metabolites increased with decreasing number of methyl group. With liver dysfunction, the plasma clearance of these metabolites also decreased and central nervous system toxicity increased. Although the antitumor activity of pentamethylmelamine is thought to be mediated by the intermediate hydroxymethyl metabolites produced by hepatic microsomal oxidation or by the formaldehyde generated, the neurological toxicity appears to depend upon the pharmacokinetics of the drug and its demethylated metabolites.

Altretamine↗