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Featured researches published by John A. Benvenuto.


Cancer | 1980

Treatment of cultured human colon carcinoma cells with fluorinated pyrimidines

Benjamin Drewinko; Li Y. Yang; D. H.W. Ho; John A. Benvenuto; Ti Li Loo; Emil J. Freireich

The shape of the initial part of the dose‐dependent response curve of LoVo cells, an established human colon carcinoma cell line, exposed for 1 hr to graded concentrations of 5‐FU depended on the medium supplement, i.e., fetal calf serum (FCS), in which the cells were treated and subsequently incubated for colony‐formation. At concentrations of 50–100 μg/ml (equivalent to peak plasma levels following an in vivo bolus dose of 15 mg/kg) cell kill was completely prevented by FCS. The serum did not contain thymidine (TdR) but had significant amounts of uridine (UR). When 5‐FU was delivered in dialyzed FCS, concentrations of 50–100 μg/ml achieved only a modest 15% cell kill after 1 hour treatment. Regardless of medium supplement, the killing effect of 5‐FU did not increase beyond concentrations greater than 2,000 μg/ml. Increasing the exposure interval dramatically increased the killing of LoVo cells by 5‐FU, although the effects of medium supplement on the degree of cell survival persisted for about 12 hours. Virtually all of the incorporated 5‐FU was transformed into 5‐FUR, and a very small proportion eventually was incorporated into nucleic acids, suggesting that the killing effect of 5‐FU on LoVo cells is mediated mostly by ribosidation and not by conversion into the deoxyribonucleoside. This conclusion is supported by the failure of 5‐FUdR to kill LoVo cells after a treatment interval of one hour, even at concentrations of 5000 μg/ml; yet after the same exposure interval, 5‐FUR effectively killed cells at concentrations of 50–100 μg/ml. TdR afforded no protection from cell kill by 5‐FU. In contrast, UR was capable of protecting LoVo cells from the lethal effects of both 5‐FU and 5‐FUR even at concentrations as low as 10 μg/ml. Ftorafur exposed to LoVo cells for 1 hour had a slight killing effect (about 20–25%) at concentrations ranging up to 2000 μg/ml. Although the lethal effect of ftorafur was slightly increased after longer periods of incubation, it failed to reach 90% even after intervals of 48 hours. The results on cellular sensitivity that we obtained for LoVo cells treated with various fluorinated pyrimidines differ substantially from those of other investigators who used different methods to assess cell killing on nonhuman and noncolonic cell systems. The predictive relevance of these data as compared to those obtained in other systems is justified by the suboptimal results with these agents in clinical practice.


Investigational New Drugs | 1992

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

John A. Benvenuto; Robert A. Newman; Gary S. Bignami; T. J G Raybould; Martin N. Raber; Laura Esparza; Ronald S. Walters

SummarySixteen 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 (t 1/2α=0.12 hr, t 1/2β=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.


Cancer Chemotherapy and Pharmacology | 1982

Pharmacokinetics and metabolism of β-2′-deoxythioguanosine and 6-thioguanine in man

Katherine Lu; John A. Benvenuto; Gerald P. Bodey; Jeffrey A. Gottlieb; Michael G. Rosenblum; Ti Li Loo

SummaryResistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, β-2′-deoxythioguanosine (β-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 β-TGdR in patients with cancer after intravenous administration. [35S]-β-TGdR (5.4 mg/kg, 200 mg/m2, 200 μCi 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 μCi 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 β-TGdR is merely a latent form of TG.


Archive | 1987

Pharmaceutical Issues in Infusion Chemotherapy Stability and Compatibility

John A. Benvenuto; Stephen C. Adams; Harish M. Vyas; Roger W. Anderson

The Increased use of small-volume infusions, continuous infusions, and individualized home care infusions in various container materials has necessitated the determination of stability and compatibility of cancer chemotherapy agents under these diverse conditions. The lack of such data can potentially lead to underdosing or administration of toxic degradation products. Because these interactions are a direct result of medication preparation, the establishment of a pharmacy-based infusion service is essential to the delivery of effective infusion therapy. Other rationale for a pharmacy-based infusion service include sterility and accuracy of drug preparaltion; central location for drug preparation and record-keeping; reduced expos:ure of other hospital personnel to cytotoxic agents; and expert knowledge of drugs, doses, fluids, and potential hazards.


Drug Metabolism Reviews | 1978

Metabolism and Disposition of Baker's Antifolate (NSC-139105), Ftorafur (NSC-148958), and Dichlorallyl Lawsone (NSC-126771) in Man

Ti Li Loo; Robert S. Benjamin; Katherine Lu; John A. Benvenuto; S. W. Hall; Eugene M. McKelvey

(1978). Metabolism and Disposition of Bakers Antifolate (NSC-139105), Ftorafur (NSC-148958), and Dichlorallyl Lawsone (NSC-126771) in Man. Drug Metabolism Reviews: Vol. 8, No. 1, pp. 137-150.


Biochemical Pharmacology | 1995

Biochemical pharmacology of penclomedine (NSC-338720)

John A. Benvenuto; Walter N. Hittelman; Leonard A. Zwelling; William Plunkett; Tej K. Pandita; David Farquhar; Robert A. Newman

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.


Anti-Cancer Drugs | 1992

Clinical pharmacokinetics of ifosfamide in combination with N-acetylcysteine.

John A. Benvenuto; Workenesh Ayele; Sewa S. Legha; Martin N. Raber; Claude Nicaise; Robert A. Newman

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.


Cancer Chemotherapy and Pharmacology | 1981

Disposition and metabolism of thiopurines - III. β-2′-Deoxythioguanosine and 6-thioguanine in the dog

Ti Li Loo; Katherine Lu; John A. Benvenuto; Michael G. Rosenblum

SummaryThe anticancer agent β-2′ deoxythioguanosine (β-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]β-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 t1/2 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 t1/2 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 t1/2 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 [814C] TG. In these studies, however, the terminal phase t1/2 of 14C in plasma was 1.9 h. Cumulative urinary excretion of the 14C was 40% in 5 h. Both TG and β-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, β-TGdR was rapidly metabolized to TG and may serve as a slow release from of TG.


American Journal of Clinical Oncology | 1985

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

Delia F. Chiuten; Manuel Valdivieso; Agop Y. Bedikian; John A. Benvenuto; Antonins Miller; Ti Li Loo; Gerald P. Bodey; Emil J. Freireich

TWENTY-SEVEN PATIENTS WITH COLORECTAL ADENOCAR-CINOMA, (12) non-small cell bronchogenie carcinoma, (11) gastric adenocarcinoma (3), and adenocarci-noma 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; thy-mine, 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.


American Journal of Clinical Oncology | 1986

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

Delia F. Chiuten; M. Valdivieso; John A. Benvenuto; Benjamin Drewinko; Agop Y. Bedikian; Gerald P. Bodey

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 doselimiting 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 ≥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.

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Ti Li Loo

University of Texas MD Anderson Cancer Center

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David Farquhar

University of Texas MD Anderson Cancer Center

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Robert S. Benjamin

University of Texas MD Anderson Cancer Center

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Katherine Lu

University of Texas MD Anderson Cancer Center

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Robert A. Newman

University of Texas MD Anderson Cancer Center

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S. W. Hall

University of Texas MD Anderson Cancer Center

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Gerald P. Bodey

University of Texas MD Anderson Cancer Center

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Agop Y. Bedikian

University of Texas MD Anderson Cancer Center

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Benjamin Drewinko

University of Texas MD Anderson Cancer Center

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