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Biomedical subjects

D E Brenner

Publications and source records attributed to D E Brenner.

At least 55 records · Page 3Linked to original sources
PubMed1991

DNA damage and cytotoxicity induced by metabolites of anthracycline antibiotics, doxorubicin and idarubicin.

This study assessed the ability of major metabolites of two types of anthracycline antibiotics, doxorubicin and idarubicin (4-demethoxydaunorubicin) to damage DNA in mouse fibrosarcoma 935.1 cells. Since DNA lesions by anthracyclines may be mediated by topoisomerase II, we also characterized the ability of the drugs to inhibit this enzyme. The C-13 alcohol and aglycone metabolites of doxorubicin and idarubicin were compared to the parent drugs in terms of induction of DNA single strand breaks measured by filter elution. In whole cells, the maximal DNA strand breakage induced by the C-13 alcohol metabolites was similar to that of their respective parent drugs. In isolated nuclei, however, the alcohol metabolites were two times more potent than the parent drugs. The aglycone metabolites produced very little damage in either whole cells or nuclei. The doxorubicin compounds differed markedly from idarubicin drugs in the way their ability to induce DNA breaks was related to cytotoxic activity. Doxorubicin and doxorubicinol cytotoxic effects (50% cell growth inhibition at 0.2 and 4 microM, respectively) coincided (in terms of drug concentrations) with the induction of significant breakage of cellular DNA. In contrast, the concentrations of idarubicin and idarubicinol needed to produce 50% growth inhibition (0.005 and 0.006 microM, respectively) were about 20 times lower than drug levels that induced significant DNA damage. All six compounds inhibited the catalytic activity of isolated topoisomerase II. While the alcohol metabolites produced this inhibition at concentrations similar to those of their parent drugs (5-10 microM), the aglycones were again much less active.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Initial clinical trial of the macrophage activator muramyl tripeptide-phosphatidylethanolamine encapsulated in liposomes in patients with advanced cancer.

A phase I clinical trial of the macrophage activator, muramyl tripeptide-phosphatidylethanolamine has been carried out in 37 patients (47 courses) at doses of 0.01-6.0 mg/m2 intravenously twice weekly for 4 weeks. Activation of peripheral blood monocytes and drug toxicity were used as the parameters to monitor the trial. Toxicity was acute systemic responses of fever, chills, and hypertension without a clear dose response. No major organ-related toxicity was seen. A dose of 4.0 mg/m2 biweekly produced activation of blood monocytes; a dose of 6.0 mg/m2 produced inhibition. There was one complete response of 3 months duration in a patient with renal cell carcinoma with pulmonary metastases. The optimum dose for phase II studies is in the range of 1-4 mg/m2 twice weekly for 4 weeks, a dose that is well tolerated.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

A phase I clinical trial of recombinant human tumor necrosis factor given daily for five days.

A phase I trial of human recombinant tumor necrosis factor (rH-TNF) has been carried out in patients with advanced solid tumors. Sixty-six courses of the drug were given by 1 h IV infusion, daily for 5 days to 33 patients at doses of 5, 10, 20, 30, 45, 60, and 80 x 10(4) U/m2/day. All patients received isotonic saline (up to 21/day) and either indomethacin or ketoprofen. Acute toxicity resembled that seen with the phase I study of a single dose (5). Dose limiting toxicity was acute, rapidly reversible, hepatic dysfunction and hypotension. Hypertension during drug infusion and dyspnea were marked in some patients. There was one complete and one minor response, both in patients with renal cell carcinoma. The dose of 80 x 10(4) U/m2/day x 5 was poorly tolerated and the recommended starting dose for phase II studies is 60 x 10(4) U/m2/day x 5. Caution is recommended in treating patients with pre-existing hepatic function abnormalities, hypertension, hypotension or significant obstructive airway disease.

Adult↗
PubMed1989

A phase II study of the efficacy of diamminedichloroplatinum (cisplatin) for the control of locally recurrent and intransit malignant melanoma of the extremities using tourniquet outflow-occlusion techniques.

A phase II trial was conducted with 15 patients (mean age of 65.7 years) with locally recurrent or intransit melanoma of the extremities. After total outflow occlusion with pneumatic tourniquet, the cell-cycle nonspecific anti-neoplastic agent cis-diamminedicholoroplatinum (CDDP) was infused intra-arterially in a mean dose of 26.7 mg/m2 per infusion (2.6 infusions per patient). The aim of this study was to determine the efficacy of CDDP infusion for control of intransit and recurrent melanoma of the extremities. Three to four weeks postinfusion, all visible residual disease was resected. Partial remissions were observed in ten patients (67%); five patients achieved stable disease status. No patient had complete regression of disease. At an average follow-up interval of 18.3 months (range 4-44 months), the mean local/regional disease-free survival was 14.8 months. Eighty per cent of patients (twelve of 15) had local/regional control of disease at an average follow-up of 14.8 months after CDDP infusion and surgical resection. Of five melanoma-related deaths, three patients had had no local/regional recurrence at the time of their demise. Three compartment syndromes resulted as a complication of the infusional therapy and occurred within 1-3 days of the treatment. In vitro growth of melanoma from lymph nodes draining the infused area was seen in all subjects studied. Outgrowth from tumor within the tourniquet infusion area was observed in two patients, both of whom experienced recurrences clinically at 24-months' postinfusion. Pharmacokinetic data of total CDDP concentrations from tissue and blood (n = 4) were available from pretreatment to 1 hour post-therapy. Biopsy data from patients pre- and post-treatment suggest substantial tumor uptake of CDDP as compared to local or distal normal skin, with minimal CDDP loss to the systemic circulation. Pharmacologic and clinical data of this phase II trial suggest that intraarterial infusion with tourniquet outflow-occlusion augments tumor tissue levels of CDDP within the infused extremity and enhances local control of high-risk and intransit disease.

Adult↗
PubMed1989

Lack of effect of treatment with human recombinant-tumour necrosis factor (HrTNF) on the binding of quinidine to alpha 1-acid glycoprotein (AGP).

Tumour necrosis factor (TNF) is known to be a key mediator in the acute phase response and its administration has been shown to cause a five fold increase in serum alpha 1-acid glycoprotein (AGP) concentration in the rat. Since, in man, plasma AGP level determines the protein binding of many important drugs (e.g. narcotic analgesics, phenothiazines, antiarrhythmics, calcium channel blockers) likely to be given to patients who will be treated with TNF, it is important to determine if TNF treatment of humans causes a similar increase in AGP concentration and drug binding. Therefore, the plasma protein binding of quinidine and the serum level of AGP were studied over a 4 day period in each of five cancer patients who were treated with human recombinant-tumour necrosis factor (HrTNF) using a dosage schedule of 6-8 x 10(+5) units/m2 daily for 5 days. It was observed that the quinidine binding ratio (the quotient of bound and free concentration in plasma) was highly correlated with the plasma concentration of AGP (r = 0.818) and that the mean pretreatment AGP concentration in the patients was about three times that found in normal subjects. However, no effects of the TNF treatment regime used in the present study could be demonstrated on either plasma AGP concentration or quinidine free fraction. These observations allow the tentative conclusion that HrTNF does not cause a significant increase in serum AGP level in cancer patients whose baseline AGP concentration is high. However, further study of the relationship between TNF treatment and serum AGP level is needed.

Adult↗
PubMed1988

Uptake and intracellular distribution of doxorubicin metabolites in B-lymphocytes of chronic lymphocytic leukemia.

The toxicity of doxorubicin metabolites was evaluated on lymphocytes of B-cell chronic lymphocytic leukemia. Only doxorubicinol was found to be cytotoxic for these lymphocytes, whereas exposure to aglycones at concentrations as high as 5 microM for 1 h had no effect on the proliferative capacity of these cells. After exposure of cells to isomolar concentrations of doxorubicin or its metabolites, uptake/retention of doxorubicinol was 23% of doxorubicin, and uptake/retention of aglycones was 5 to 13% of doxorubicin. Seventy to 90% of doxorubicin and 60 to 90% of doxorubicinol taken up/retained by the cells were detected in the cell nuclear fraction, whereas only 20 to 40% of the aglycones were localized in the cell nucleus. Cytotoxicity of metabolites was generally related to the proportion of drug taken up/retained by the cells and localized to the nuclei. The low uptake and nuclear localization may be at least partially responsible for the lack of cytotoxicity of aglycones on B-lymphocytes from chronic lymphocytic leukemia.

B-Lymphocytes↗
PubMed1988

Effect of phenytoin on the pharmacokinetics of doxorubicin and doxorubicinol in the rabbit.

Doxorubicin is metabolized extensively to doxorubicinol by the ubiquitous aldoketoreductase enzymes. The extent of conversion to this alcohol metabolite is important since doxorubicinol may be the major contributor to cardiotoxicity. Aldoketoreductases are inhibited in vitro by phenytoin. The present study was conducted to examine the effect of phenytoin on doxorubicin pharmacokinetics. Doxorubicin single-dose pharmacokinetic studies were performed in 10 New Zealand White rabbits after pretreatment with phenytoin or phenytoin vehicle (control) infusions in crossover fashion with 4-6 weeks between studies. Infusions were commenced 16 h before and during the course of the doxorubicin pharmacokinetic studies. Phenytoin infusion was guided by plasma phenytoin estimation to maintain total plasma concentrations between 20 and 30 micrograms/ml. Following doxorubicin 5 mg/kg by i.v. bolus, blood samples were obtained at intervals over 32 h. Plasma doxorubicin and doxorubicinol concentrations were measured by HPLC. The mean plasma phenytoin concentrations ranged from 17.4 to 33.9 micrograms/ml. Phenytoin infusion did not alter doxorubicin pharmacokinetics. The elimination half-life and volume of distribution were almost identical to control. Clearance of doxorubicin during phenytoin administration (60.9 +/- 5.8 ml/min per kg, mean +/- SE) was similar to that during vehicle infusion (67.5 +/- 5.4 ml/min per kg). Phenytoin administration was associated with a significant decrease in doxorubicinol elimination half-life from 41.0 +/- 4.8 to 25.6 +/- 2.8 h. The area under the plasma concentration/time curve (AUC) for doxorubicinol decreased significantly from 666.8 +/- 100.4 to 491.5 +/- 65.7 n.h.ml-1. These data suggest that phenytoin at clinically relevant concentrations does not alter the conversion of doxorubicin to doxorubicinol in the rabbit. The reduction in the AUC for doxorubicinol caused by phenytoin appears to be due to an increased rate of doxorubicinol elimination. Phenytoin or similar agents may have the effect of modifying doxorubicinol plasma concentrations by induction of doxorubicinol metabolism rather than by inhibition of aldoketoreductase enzymes.

Alcohol Dehydrogenase↗
PubMed1988

The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin in rabbits.

The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin was studied in six female New Zealand white rabbits. Plasma pharmacokinetic data were first obtained from rabbits given 3 mg/kg doxorubicin. After 1 month, the same rabbits were treated with ranitidine, 2.5 mg/kg or 25 mg/kg, before and during doxorubicin administration. The plasma doxorubicin assays to determine pharmacokinetic parameters were repeated. Drug toxicity was evaluated using complete blood counts, and hepatic function was measured using a 14C-aminopyrine breath test. High-dose ranitidine increased the total exposure to doxorubicin (area under the curve of doxorubicin alone = 1.44 +/- 0.88 microM.h/ml vs 4.49 +/- 2.35 microM.hr/ml for doxorubicin given with high-dose ranitidine; P = 0.06). Low-dose ranitidine did not alter doxorubicin pharmacokinetics. Exposure to doxorubicinol was altered by either high-dose or low-dose ranitidine. 14C-Aminopyrine half-life was altered by a ranitidine dose of 25 mg/kg (aminopyrine half-life after placebo control = 97 +/- 6 min as against aminopyrine half-life after ranitidine = 121 +/- 7 min; mean +/- SEM; P less than 0.02). Low-dose ranitidine did not exacerbate doxorubicin-induced myelosuppression. High-dose ranitidine enhanced doxorubicin-induced erythroid suppression while sparing the myeloid series. At cytochrome P-450-inhibitory doses, ranitidine's effects upon doxorubicin plasma pharmacokinetics are similar to those previously seen with cimetidine. These changes did not appear to alter drug detoxification and are not related to microsomal inhibition of doxorubicin detoxification. Low doses of ranitidine do not alter doxorubicin plasma pharmacokinetics or toxicity in rabbits.

Aminopyrine↗
PubMed1988

Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol.

Doxorubicin (former generic name, adriamycin), a highly effective anticancer drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin. Doxorubicinol was markedly more potent than doxorubicin at compromising both systolic and diastolic cardiac function. Similarly, doxorubicinol was much more potent than doxorubicin at inhibiting the calcium pump of sarcoplasmic reticulum [ATP phosphohydrolase (Ca2+-transporting), EC 3.6.1.38], the Na+/K+ pump of sarcolemma [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37], and the F0F1 proton pump of mitochondria [ATP phosphohydrolase (H+-transporting, EC 3.6.1.34]. Our finding that this highly toxic metabolite was produced by cardiac tissue exposed to doxorubicin suggests that doxorubicinol could accumulate in the heart and contribute significantly to the chronic cumulative cardiotoxicity of doxorubicin therapy. Our observation that doxorubicin was more potent than doxorubicinol in inhibiting tumor cell growth in vitro suggests that the cardiotoxicity of doxorubicin is dissociable from its anticancer activity.

Animals↗
PubMed1987

The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. A correlative study of cardiac muscle with isolated membrane fractions.

Doxorubicin (adriamycin) is a highly effective cancer chemotherapeutic drug but its clinical utility is limited by its cardiotoxicity. Doxorubicinol, the major metabolite of doxorubicin, is up to 10 times more potent than doxorubicin at inhibiting isometric contraction of the papillary muscle isolated from the right ventricle of rabbit heart. Doxorubicinol also increases resting tension of isolated cardiac muscle indicative of incomplete relaxation between contractions, a characteristic of doxorubicinol but not of doxorubicin. This study assesses the effect(s) of doxorubicinol on a variety of ion pumps which may explain, in part, the action of the metabolite in the intact muscle. We find the doxorubicinol is a potent inhibitor (IC50 less than 5 micrograms/ml) of calcium-stimulated ATPase activity of sarcoplasmic reticulum from canine heart and rabbit skeletal muscle. At comparable levels, doxorubicinol is also a potent inhibitor of (Na + K)-ATPase of cardiac sarcolemma and the Mg-dependent ATPase activity referable to the F0F1 proton pump of mitochondria. For each of these ion pumps, doxorubicinol is at least 80 times more potent an inhibitor than doxorubicin. Doxorubicinol, between 10 and 50 micrograms/ml, increases resting tension up to 4-fold in isolated papillary muscles cyclically contracting at 30 times/min. Resting stress is relatively insensitive to doxorubicin. Thus, doxorubicinol is a potent inhibitor of several key cationic pumps that directly or indirectly regulate cell calcium and inhibits relaxation in the isolated fiber preparation. These observations add a new dimension to understanding the cardiotoxicity of doxorubicin.

5'-Nucleotidase↗
PubMed1987

Effect of allyl alcohol-induced sublethal hepatic damage upon doxorubicin metabolism and toxicity in the rabbit.

A model of hepatic dysfunction in vivo has been developed in rabbits to determine the effects of sublethal hepatocellular necrosis upon doxorubicin pharmacology. Eight New Zealand white rabbits were given 3 mg/kg doxorubicin i.v. Plasma doxorubicin and metabolite pharmacokinetics were determined and toxicity assessed by nadir complete blood counts. Hepatic function was assessed by the pulmonary excretion rate of 14CO2 from [14C]aminopyrine. Hepatocellular necrosis was produced by i.v. injection of 1.35 mg/kg of a 2% allyl alcohol solution. Doxorubicin administration and pharmacokinetics were repeated. Doxorubicin enhances the hepatotoxicity of allyl alcohol. Hepatocellular necrosis does not alter the plasma pharmacokinetics of doxorubicin but does increase the plasma exposure of doxorubicinol. Doxorubicin-induced myelosuppression is enhanced by allyl alcohol pretreatment. These data suggest that in circumstances of reduced hepatocellular volume or acute hepatocellular necrosis, a key plasma marker of doxorubicin-induced acute toxicity may be doxorubicinol.

1-Propanol↗
PubMed1987

Simultaneous radiation and chemotherapy for advanced carcinoma of the cervix.

Six patients with poor prognosis carcinoma of the cervix were treated with external radiation therapy simultaneously with cisplatin, bleomycin, and vincristine. Toxicity was very mild with nausea and vomiting and mild myelosuppression being the major toxicities. At a median of 36 months follow-up, four of six patients are alive, three with no evidence of disease. The median survival after diagnosis is 25+ months. The data suggest that radiation therapy and cytotoxic therapy administered together in patients with advanced cervix carcinoma is well tolerated. Further study to determine therapeutic efficacy is warranted.

Adenocarcinoma↗
PubMed1987

Combination chemotherapy for patients with advanced carcinoma of the cervix: trial of mitomycin-C, vincristine, bleomycin, and cisplatin.

Sixteen patients with metastatic or recurrent carcinoma of the cervix were treated with combination chemotherapy consisting of mitomycin-C, vincristine, bleomycin, and cisplatin. Seven of 14 (50%) evaluable patients responded. In 2 patients all measurable disease resolved. Median duration of response was 4.5 months. Toxicity was severe and consisted of myelosuppression, pulmonary fibrosis, nausea, vomiting, stomatitis, asthenia, and fever. Two treatment-related deaths occurred. This combination chemotherapy regimen appears to have a response rate similar to other cisplatin containing regimens. Response durations were short and toxicity was severe.

Adult↗
PubMed1987

Approaches to the problem of individual doxorubicin dosing schedules.

Doxorubicin is one of the most commonly used antineoplastic agents today. Dosing schedules are inexact and there remains a need to develop predictive models for its administration. Data from prior work in humans is difficult to interpret because of poor patient selection, poor drug assays, lack of knowledge of metabolite toxicity, concurrent treatment with other hepatically metabolized drugs, and individual pharmacogenetics which are poorly described. We have developed a rabbit model of in vivo drug pharmacokinetics in the setting of enzyme inhibition and sublethal hepatocellular necrosis. Our data suggest that the rabbit may be used as a model of hepatic drug metabolism and that changes in drug pharmacokinetics and pharmacodynamics in isolated hepatic disease may be simulated in the rabbit. The results obtained may be applied in more directed and controlled studies in humans.

Animals↗