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D S Martin

Publications and source records attributed to D S Martin.

At least 19 recordsLinked to original sources
PubMed1992

A phase II trial of biochemical modulation using N-phosphonacetyl-L-aspartate, high-dose methotrexate, high-dose 5-fluorouracil, and leucovorin in patients with adenocarcinoma of unknown primary site.

BACKGROUND: 5-Fluorouracil (5-FU) has modest activity as a single agent in a number of human adenocarcinomas. The technique of biochemical modulation has been used preclinically to increase the activity of 5-FU. METHODS: With doses based on a Phase I study, the authors performed a Phase II trial in patients with advanced metastatic adenocarcinoma of an unknown primary site using N-phosphonacetyl-l-aspartate (PALA), methotrexate (MTX), 5-FU, and leucovorin. In some patients, 5-phosphoriosyl-l-pyrophosphate (PRPP) and uridine triphosphate (UTP) metabolite pools were assayed before and after PALA and MTX to assess metabolite pool shifts. RESULTS: Twenty-one patients were treated in this Phase II trial. Toxicity was tolerable. Biopsy specimens of tumor tissue showed increases in PRPP and decreases in UTP levels in two of three and three of four patients, respectively. However, only one objective response was seen, which is not different from that expected with 5-FU alone. CONCLUSIONS: Expected PRPP and UTP metabolite pool shifts were seen when biochemical modulation was performed with these drugs according to this schedule. Because toxicity was mild, more intense dose schedules of 5-FU are planned for future studies.

Adenocarcinoma↗
PubMed1992

Biochemical modulation of tumor cell energy: regression of advanced spontaneous murine breast tumors with a 5-fluorouracil-containing drug combination.

This report describes a highly active chemotherapeutic drug combination, consisting of N-(phosphonacetyl)-L-aspartate plus 6-methylmercaptopurine riboside plus 6-aminonicotinamide plus 5-fluorouracil, in CD8F1 mice bearing spontaneous, autochthonous, breast tumors or first-passage advanced transplants of these spontaneous tumors. The combination and sequence of administration of these drugs were selected on the basis of known potentiating biochemical interactions. High performance liquid chromatography and nuclear magnetic resonance spectroscopy measurements of biochemical changes resulting from treatment with N-(phosphonacetyl)-L-aspartate plus 6-methylmercaptopurine riboside plus 6-aminonicotinamide indicated a severe depletion of cellular energy levels in the treated tumors. 6-Aminonicotinamide produced a severe block of the pentose shunt, and 5-fluorouracil severely inhibited both thymidylate synthase and thymidine kinase in the treated tumors. This quadruple drug combination, administered on a 10-11-day schedule, produced an impressive partial tumor regression rate of 67% of large, spontaneous, autochthonous, murine breast tumors and a tumor regression rate of 74% of first-passage transplants of the spontaneous breast tumors.

6-Aminonicotinamide↗
PubMed1992

Biochemical modulation of 5-fluorouracil with leucovorin or delayed uridine rescue. Correlation of antitumor activity with dosage and FUra incorporation into RNA.

Two strategies for modulation of 5-fluorouracil (FUra) activity were compared in vivo in advanced murine CD8F1 breast tumors with regard to three parameters: chemotherapeutic activity, inhibition of thymidylate synthase (TSase) activity, and incorporation of FUra into RNA, (FU)RNA. Inhibition of TSase by FUra was modulated by leucovorin (LV), and the incorporation of FUra into RNA was increased by the administration of otherwise lethal doses of FUra followed by uridine "rescue". Thymidylate synthase activity was inhibited substantially (49%) by low-dose FUra at 25 mg/kg, but was not further enhanced (48%) by repeated daily treatments at the same dose (FUra25 x 4). Inhibition of TSase was somewhat enhanced (55%) by the addition of LV to FUra25 x 4, and a greater therapeutic effect was obtained with FUra25 x 4 + LV over FUra25 x 4 alone. FUra as a single agent at the maximum tolerated weekly dose of 100 mg/kg inhibited TSase activity 66-73%. This inhibition was further enhanced slightly by the addition of LV (71-82%), and its therapeutic efficacy was greater than with FUra25 x 4 with or without LV. However, in contrast to low dose FUra25 x 4, the antitumor effect of FUra100 was not enhanced by LV. (FU)RNA increased with FUra dose from 0.4 (FUra25) to 2.2 nmol/mg DNA (FUra100). At a very-high-dose of FUra (200-225 mg/kg) followed by uridine "rescue", TSase inhibition was not further enhanced, but both (FU)RNA (4.8 nmol/mg DNA) and the therapeutic efficacy were increased. Since TSase could not be further inhibited at doses above FUra100, the increased chemotherapeutic efficacy correlated with increased (FU)RNA.

Animals↗
PubMed1992

Sympathetic nervous system activation by glutamate injections into the paraventricular nucleus.

The purpose of the present study was to determine the overall cardiovascular and sympathetic nervous system responses to stimulation of neuronal cell bodies in the paraventricular nucleus (PVN) of the hypothalamus. Bilateral microinjections (50 nl) of monosodium glutamate or sodium acetate were made into the PVN of conscious unrestrained rats. Blood pressure, heart rate and plasma concentrations of norepinephrine and epinephrine were measured. The injection of sodium acetate as an osmotic control was without effect on any of the recorded variables. In contrast, the injections of glutamate were associated with a rapid increase in both blood pressure and heart rate. At doses of 15, 25, and 50 nmol blood pressure increased by 13 +/- 2, 14 +/- 3 and 16 +/- 1 mmHg while heart rate increased by 64 +/- 15, 73 +/- 8 and 50 +/- 8 bpm. These responses were associated with increases in plasma norepinephrine concentrations of 51 +/- 8, 100 +/- 16 and 62 +/- 13 pg/ml while epinephrine concentrations rose by 42 +/- 17, 58 +/- 18 and 38 +/- 17 pg/ml. The responses of glutamate (25 nmol) were not affected by blockade of vascular vasopressin receptors with d(CH2)5Tyr(Me)AVP (10 micrograms/kg) (blood pressure: pre 15 +/- 3 vs post 13 +/- 3 mmHg, heart rate: pre 77 +/- 9 bpm vs post 91 +/- 7 bpm, plasma norepinephrine: pre 106 +/- 22 vs post 121 +/- 28 pg/ml and plasma epinephrine: pre 61 +/- 25 vs post 34 +/- 30 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin Receptor Antagonists↗
PubMed1992

Measurement of the distribution of [3H]bicuculline microinjected into the rat hypothalamus.

The purpose of this study was to measure the distribution of a radiolabeled drug [3H]bicuculline methylchloride ([3H]BMC) following microinjection into the supraoptic nuclei (SON) and the dorsal hypothalamus of conscious rats. The anteroposterior (AP) distribution was measured using liquid-scintillation counting while computer-assisted densitometry was used to measure the mediolateral (ML) and dorsoventral (DV) distribution of silver grains on autoradiograms. Following a 50-nl microinjection into the SON, 90% of the detected tracer was found within 0.6 +/- 0.1 mm (n = 5) of the injection site. Using the same volume, the pattern of distribution of 90% of the detected tracer in the SON was not significantly altered when rats received a microinfusion over 10 min (n = 5) or a bolus microinjection with a 10 min waiting period (n = 6) prior to death. Following a 100-nl microinfusion over 20 min into the dorsal hypothalamus, 90% of the detected radiolabel was found within 0.6 +/- 0.1 mm (n = 7) of the injection site, in a spherical pattern of distribution. Although caution must be used in extrapolating these results to other drugs, these data suggest that intraparenchymal microinjections of 50- and 100-nl volumes are suitable for drug localization in studies using microinjection techniques for conscious rats.

Animals↗
PubMed1992

Allozyme comparison of three Trypanosoma species (Kinetoplastida: Trypanosomatidae) of toads and frogs by starch-gel electrophoresis.

Six metabolic enzymes, glucose-6-phosphate dehydrogenase, glucosephosphate isomerase, isocitrate dehydrogenase, malate dehydrogenase, phosphoglucomutase, and purine nucleoside phosphorylase, from clonal isolates of 3 presumptive species of Trypanosoma (T. fallisi, T. ranarum, and T. rotatorium) from 3 anuran hosts (Bufo americanus, Rana clamitans, and Rana catesbeiana) were compared using starch-gel electrophoresis. Although bands were shared among the different zymodemes of isolates of the same host genus, low genetic polymorphism of the enzyme loci was observed with few apparent shared bands between samples isolated from frogs and toads. A distance value calculated between toad and frog trypanosome isolates suggests the likelihood of long-time separation of species. Cluster analysis based on overall similarity distinguished the trypanosomes of toads and frogs as separate taxa, suggesting that host specificity and observed morphological differences are consistent with heritable allozyme differences.

Alleles↗
PubMed1992

Overview of N-(phosphonacetyl)-L-aspartate + fluorouracil in clinical trials.

The clearest example of successful biochemical modulation of cancer chemotherapy in the laboratory, followed by initial failure to reproduce successful therapeutic results in the clinic, and then eventually followed by clinical success, is that of the combination of N-(phosphonacetyl)-L-aspartate (PALA) and fluorouracil (5-FU). This review covers the biochemistry involved, the preclinical findings, the many clinical trials, and explains the differences between the initial unsuccessful and the later successful clinical studies. The overall findings demonstrate that, to be successful, the design of modulation-based clinical trials should adhere to the principles determined in preclinical studies.

Antimetabolites, Antineoplastic↗
PubMed1992

Modulation of fluorouracil by N-(phosphonacetyl)-L-asparate: a review.

N-(phosphonacetyl)-L-asparate (PALA), a potent inhibitor of de novo pyrimidine synthesis, was demonstrated in preclinical studies to enhance the therapeutic activity of fluorouracil (5-FU). However, the initial clinical trials with the combination failed to conform to these experimental findings. Very recent clinical studies, employing for the first time the principles for the enhanced therapeutic interaction determined in the preclinical studies, have now reported enhanced efficacy with the PALA-FU combination. Reviewing the lessions of the PALA-FU experience, this article explains the potential benefits as well as the need for biochemical modulation in cancer chemotherapy, the need for the appropriate dosage ratio between agents in modulation-based clinical trials, and the necessity to determine in patients, by direct biochemical measurements at the tissue level, the dose and temporal relationship between agents that reproduces the pertinent biochemical changes in human tumors that produced the therapeutic success of that particular drug combination in the preclinical model.

Animals↗
PubMed1992

Current imaging concepts of thoracic intervertebral disks.

This article reviews the current concepts of thoracic herniated disks using the radiologic literature as well as our own experience with more than 100 thoracic HNPs. The relative frequency of asymptomatic thoracic HNPs is documented. Points of interest include the optimal technique, criteria for interpretation, strengths and weaknesses of various imaging modalities, including water-soluble myelography, CT myelography, and magnetic resonance imaging. Additionally, the protean clinical manifestations of thoracic HNPs and current operative management are briefly addressed.

Artifacts↗
PubMed1991

Loss of murine tumor thymidine kinase activity in vivo following 5-fluorouracil (FUra) treatment by incorporation of FUra into RNA.

The effects of 5-fluorouracil (FUra) treatment on thymidine kinase (TKase) activity were examined in vivo in CD8F1 mice bearing first generation CD8F1 mouse mammary tumors. TKase activity was not affected by low dose FUra25 (25 mg/kg), a dose which substantially inhibited thymidylate synthase (TSase), but was severely inhibited 24 hr following treatment with FUra100, a weekly maximally tolerated dose, as judged by activity measurements and labeling of DNA with [3H]thymidine. The amount of (FU)RNA was increased markedly with increasing FUra dose from 0.4 nmol/mg DNA at FUra25 to 2.2 nmol/mg DNA at FUra100. At FUra100, TKase activity gradually declined over 24 hr to less than 10% of the control value, remained low for a further 48 hr, and then was gradually restored to control levels by 168 hr. The loss of TKase activity followed the incorporation of FUra into RNA which peaked at 4-5 hr. TKase activity was not restored by removal of endogenous inhibitors but was restored by treatment with uridine. TKase activity was not inhibited by therapeutic levels of methotrexate (300 mg/kg). TKase from murine colon 38 carcinoma was also severely inhibited, but the activity from colon 26 was only partially (50%) inhibited. Ornithine decarboxylase was also inhibited by FUra100 treatment in the CD8F1 tumor. These results demonstrate that certain short-lived, proliferation-related enzymes are affected by FUra doses higher than those required for TSase inhibition, and this effect appears to correlate with incorporation of FUra into RNA. Thus, in some tumors high doses of FUra can inhibit salvage as well as de novo synthesis of thymidylate providing an increased block of DNA synthesis and increased therapeutic advantage.

Animals↗
PubMed1991

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine riboside: optimization of 6-methylmercaptopurine riboside dose and schedule through biochemical analysis of sequential tumor biopsy specimens.

Preclinical and clinical studies demonstrate that the selective antitumor activity of fluorouracil (5-FU) is enhanced by agents which perturb certain intracellular nucleotide pools. We previously demonstrated that the combination of N-phosphonacetyl-L-aspartate (PALA), which depletes pyrimidine nucleotide pools, and 5-FU yielded a 43% response rate among 37 assessable patients with colorectal carcinoma. In preclinical tumor models, 6-methylmercaptopurine riboside (MMPR), an inhibitor of purine synthesis, elevates phosphoribosylpyrophosphate (PRPP) pools and promotes the anabolism of 5-FU to fluorinated nucleotides. In vivo, the addition of MMPR enhances the therapeutic efficacy of PALA-5-FU. In a phase I trial, we sought to determine the optimal dose and schedule of MMPR in combination with PALA (250 mg/m2 on day 1) and 5-FU (1300 mg/m2 by 24-hour infusion on day 2). MMPR (75-225 mg/m2) was given intravenously on day 1 to 27 patients with solid tumors (15 colorectal, seven breast, five other). Toxic effects were mild to moderate and included leukopenia, mucositis, nausea, or rash. Two of seven patients given MMPR at 225 mg/m2 had grade 3 diarrhea. PRPP was measured using a [14C]orotic acid 14CO2 release assay in tumor biopsy specimens obtained before and 12 hours and 24 hours after MMPR doses were given to 20 patients. The addition of MMPR elevated PRPP pools in human solid tumors. At 12 hours after treatment, two (50%) of four patients showed a twofold or greater elevation of PRPP at the MMPR dose level of 75 mg/m2; a similar elevation was observed in five (71%) of seven patients given 150 mg/m2 MMPR and in three (43%) of seven patients given 225 mg/m2 MMPR. At 24 hours after treatment, results for the respective dose levels of MMPR were two (33%) of six patients, one (20%) of five patients, and four (57%) of seven patients. Administration of the two highest MMPR dose levels appeared to result in a greater increase in tumor PRPP levels. However, toxicity was greater at the 225 mg/m2 dose level; therefore, the 150 mg/m2 dose level was favored. Tumor levels of PRPP decreased between 12 hours and 24 hours in nine (56%) of 16 patients. This time course indicates that MMPR should be administered at the beginning of the 24-hour infusion of 5-FU.

Adult↗
PubMed1991

In vivo monitoring of changes in 5-fluorouracil metabolism induced by methotrexate measured by 19F NMR spectroscopy.

We have used in vivo 19F NMR spectroscopy to study the metabolism of 5-fluorouracil (FUra) in tumors with and without pretreatment with methotrexate (MTX). Using the CD8F1 murine mammary tumor as an in vivo model, we observed signals from FUra, alpha-fluoro-beta-alanine (F beta ALA), alpha-fluoro-beta-ureidopropionic acid (FUPA), and 5-fluorouracil-nucleotides (FUN) after intravenous or intraperitoneal injection of 150 mg/kg FUra. Formation of FUN was increased about 1.7-fold in CD8F1 tumor with methotrexate pretreatment as determined by acid extraction and HPLC analysis. A comparison of in vivo NMR spectra from FUra and sequential MTX + FUra-treated tumors showed a significantly higher ratio of the FUN signal to the initial total 19F signal in the MTX + FUra-treated tumors (p less than 0.001) for animals receiving FUra either intravenously or intraperitoneally. In addition, tumors treated with MTX + FUra had significantly longer time durations during which FUN was detected, independent of the mode of administration. These experiments indicate that in vivo 19F NMR spectroscopy can be used to noninvasively monitor alterations of 5-fluorouracil metabolism that occur with administration of modulating agents such as methotrexate. Further studies, in both murine tumor models and patients, are indicated to determine if these results can be correlated with tumor response.

Animals↗
PubMed1991

Development of Trypanosoma fallisi in the leech, Desserobdella picta, in toads (Bufo americanus), and in vitro. A light and electron microscopic study.

The development of Trypanosoma fallisi of Bufo americanus from Algonquin Park, Ontario was studied by light and electron microscopy in blood culture, in its leech vector Desserobdella (= Batracobdella) picta, and in its toad host. In culture, bloodstream trypomastigotes transformed within one day to elongate epimastigotes which divided into rosettes. These gave rise to amastigotes, spheromastigotes, stumpy and elongate epimastigotes, and slender metacyclic trypomastigotes over a 4- to 6-day period. Development in the leech crop was similar to that in culture, with fewer amastigotes and no spheromastigotes observed. The stages in the leech were similar in size to their culture counterparts, except for metacyclic trypomastigotes, which were larger in culture. Culture and leech stages possessed a well developed cytostome-cytopharyngeal complex and prominent reservosomes. The kinetoplast of crop stages was small with a rectangular profile, but became larger and basket-like in the proboscis forms. Migration of trypanosomes to the proboscis appeared to depend on the rate of digestion of the bloodmeal. Flagellates in the leech were also characterized by the presence of intracellular microorganisms. Development of culture forms to mature stages in the toad was completed within 8 days postinoculation, with the organisms transforming into the typical "C"-shape with a large square kinetoplast. Natural infection of B. americanus was detected at 3 days postfeeding by D. picta and the resulting bloodstream trypomastigotes developed more slowly than inoculated cultured stages.

Animals↗
PubMed1991

Enhancement of anticancer agent activity by selective inhibition of rapidly proliferating tissues of the host.

Most cytotoxic drugs used in cancer therapy do not discriminate between neoplastic and normal proliferating cells. To avoid irreversible damage to vital host tissues, such as bone marrow and intestine, drugs must be administered at dosages which usually prove insufficient to eradicate all of the neoplastic cells present. This review focuses on an approach to improve cancer chemotherapy by selectively protecting normal, proliferating cells during treatment, thereby permitting the administration of otherwise lethal doses of drug. Preclinical in vivo studies of cytokinetic modulation with interferon, or L-histidinol, as well as recent clinical studies of interferon modulation of the activity of 5-fluorouracil are reviewed.

Animals↗
PubMed1991

Whole body vascular capacitance response to vasopressin is mediated by autonomic function.

Effects of intravenous infusions of arginine vasopressin (AVP) on whole body vascular capacitance were determined in anesthetized cats when autonomic nervous system function was intact and, in other cats, when reflexes were blocked by the ganglionic blocking agent pentolinium. With the use of the constant cardiac output-reservoir technique, changes in reservoir volume were assumed to reflect reciprocal changes in whole body vascular capacitance. Relationships between the dose of AVP and the plasma concentration of the peptide achieved during infusions were not significantly different in the two groups of animals. Blood pressure responses to AVP were greater, whereas heart rate responses to the peptide were abolished in ganglion-blocked cats. In cats with intact autonomic function, reservoir volume decreased by 1.6, 4.2, and 7.8 ml/kg at AVP doses of 1, 10, and 100 ng.kg-1.min-1, respectively. In contrast, in ganglion-blocked cats, reservoir volume did not change significantly at 1.0 and 10 ng.kg-1.min-1 of AVP, and the highest dose caused a much smaller change in volume (3 ml/kg) than that observed in cats with intact autonomic function (7.8 ml/kg). Systemic compliance was unchanged by AVP in both groups of animals, suggesting that the increases in whole body vascular capacitance were likely due to changes in unstressed volume. The results suggest that reflexively mediated changes in autonomic function increase whole body vascular capacitance during elevations in the circulating levels of AVP to plasma concentrations that are biologically relevant. These findings may explain how AVP decreases cardiac output in animals with an intact autonomic nervous system.

Animals↗
PubMed1991

Cardiovascular responses to bicuculline in the paraventricular nucleus of the rat.

The present study was undertaken to determine whether gamma-aminobutyric acid in the paraventricular nucleus contributes to the regulation of cardiovascular function. Blood pressure and heart rate were recorded and plasma catecholamines were measured in conscious rats receiving microinfusions of either artificial cerebrospinal fluid or a gamma-aminobutyric acid antagonist, bicuculline methiodide, bilaterally into the paraventricular nucleus. Artificial cerebrospinal fluid had no effect on any of the recorded variables. In contrast, infusion of bicuculline into the region of the paraventricular nucleus produced increases in blood pressure (20 +/- 2 mm Hg), heart rate (110 +/- 11 beats/min), and plasma concentrations of norepinephrine (640 +/- 107 pg/ml) and epinephrine (1,266 +/- 267 pg/ml). Pretreatment with a ganglionic blocking agent abolished both the blood pressure (-1 +/- 2 mm Hg) and heart rate (5 +/- 18 beats/min) effects. Bilateral adrenal medullectomy reduced the changes in plasma norepinephrine concentrations (81 +/- 14 pg/ml) significantly and abolished the changes in plasma epinephrine concentrations (5 +/- 4 pg/ml). Conversely, adrenal medullectomy reduced the pressor effects (18 +/- 2 mm Hg) only slightly while the heart rate responses were attenuated (42 +/- 9 beats/min) by approximately 50%. These results suggest that an endogenous gamma-aminobutyric acid system exerts a tonic inhibitory effect on the sympathetic nervous system at the level of the paraventricular nucleus of the hypothalamus.

Adrenal Medulla↗