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Biomedical subjects

D S Martin

Publications and source records attributed to D S Martin.

At least 145 records · Page 8Linked to original sources
PubMed1989

Inhibition by methotrexate of the stable incorporation of 5-fluorouracil into murine bone marrow DNA.

As a consequence of the inhibition of de novo purine synthesis by methotrexate (MTX) there is an increase in 5-phosphoribosyl-1-pyrophosphate (PRPP) concentration. In cells where 5-fluorouracil (FUra) is activated via orotate phosphoribosyltransferase (OPRtase), increased PRPP results in greater conversion of FUra to nucleotides. In the murine CD8F1 breast tumor system, MTX markedly enhances the antitumor activity of FUra, increasing both the activation of FUra to FUMP and the incorporation of FUTP into RNA. However, in contrast to reported tumor tissue culture studies, MTX pretreatment in vivo prevents the stable incorporation of FUra into CD8F1 bone marrow DNA. Pretreatment with MTX (300 mg/kg) 2.5 hr prior to [3H]FUra (100 mg/kg), with a 2-hr labeling, reduced the level of FUra in DNA from 921 pmol to 66 pmol/mg of DNA. Without MTX pretreatment, 59% of the total incorporation of FUra into nucleic acids was into DNA when FUra was administered. After MTX the percentage of incorporation into DNA was reduced to 9%. Additionally, the ratio of [3H]FUra to 32P in DNA when both were given simultaneously was reduced by greater than 90%, suggesting that MTX must be specifically blocking the incorporation of FUra rather than nonspecifically preventing its incorporation by inhibiting DNA synthesis. In contrast, MTX failed to reduce the formation of DNA containing fluorouracil residues from FdUrd. To test whether MTX prevents the initial incorporation of FUra into DNA, or acts to enhance removal by the DNA glycosylase repair system, DNA was prelabeled in vivo with [3H]FUra, and MTX or MTX plus dThd was then administered. The level of FUra in bone marrow DNA was not reduced by subsequent treatment with MTX, or MTX plus dThd, indicating that MTX does not enhance the removal of FUra from DNA. The level of total free fluorodeoxynucleotides formed from FUra was reduced by two-thirds following MTX pretreatment, suggesting that the action of MTX in preventing the stable incorporation of FUra into DNA was to reduce the availability of FdUTP.

Animals↗
PubMed1989

Use of oral uridine as a substitute for parenteral uridine rescue of 5-fluorouracil therapy, with and without the uridine phosphorylase inhibitor 5-benzylacyclouridine.

Initial clinical trials have demonstrated that uridine (Urd) rescue given i.v. over at least 3 days can ameliorate 5-fluorouracil (FUra) toxicity; to avoid Urd-induced phlebitis in the peripheral veins of patients, a central vein is used. The latter necessity, along with the need for 3 days of i.v. administration, makes Urd rescue by parenteral means a cumbersome and complicated clinical procedure. It would appear preferable to use oral Urd; however, the oral Urd dose in the clinic is limited, as high doses cause diarrhea. Therefore, using a tumor-bearing murine model we investigated as to whether low doses of oral Urd coupled with a Urd phosphorylase inhibitor benzylacyclouridine (BAU), would effect safe rescue of FUra toxicity with preservation of antitumor activity. A high-dose FUra-containing drug combination that included parenteral Urd rescue was used as a control; other groups of tumor-bearing mice received the same drug combination, except that p.o. Urd was substituted for i.p. Urd. In the absence of BAU, p.o. Urd could effect rescue while maintaining an antitumor effect comparable to that obtained with i.p. Urd. When given concomitantly with BAU, a 50% reduction in the oral Urd dose (i.e., from 4,000 to 2,000 mg/kg) enabled the achievement of a comparable therapeutic index. Intraperitoneal Urd produces very high (6-8 mM) plasma and tissue Urd levels, which remain above 100 microM for at least 6 h. In contrast, neither oral Urd nor oral BAU alone raised plasma Urd concentrations above about 50 microM. However, the combination of oral Urd plus oral BAU gave a peak plasma Urd level of about 300 microM, and the level was maintained above 100 microM for 6 h. Following oral Urd administration, gut tissue levels of Urd were in the mM range and those of BAU were in the range of 10-20 micrograms/g tissue, a level sufficient to result in substantial inhibition of Urd phosphorylase. Oral Urd plus oral BAU appears to be a promising clinical alternative to parenteral administration of Urd for selective rescue of FUra toxicity.

Animals↗
PubMed1989

Effect of uridine diphosphoglucose on levels of 5-phosphoribosyl pyrophosphate and uridine triphosphate in murine tissues.

The purpose of the present investigation was to determine whether a single bolus intravenous injection (2000 mg/kg) of uridine diphosphoglucose (UDPG) could affect levels of PRPP in a transplanted mammary adenocarcinoma and in liver of CD8FI mice. Six hours following a single intravenous injection of UDPG, 2000 mg/kg, tumor PRPP was lowered to 80 pmol/mg protein, a 53% decrease compared to saline control tumors. Liver was more sensitive than tumor to the 5-phosphoribosyl pyrophosphate (PRPP)-depleting effects of a single bolus intravenous injection of UDPG, since significantly lower levels of PRPP were found in liver, but not in tumor, at doses of 500-1000 mg/kg of UDPG. Maximal depression (30% of saline control) or PRPP occurred in liver 6 hr after intravenous UDPG at 1000-2000 mg/kg. Enhanced levels of UDPG in plasma (half-life less than 10 min) and tumor was detected at 30 min after intravenous UDPG at 2000 mg/kg. There was no detectable increase in endogenous levels of UDPG in liver at this time, probably as a result of rapid metabolism of UDPG by liver. At this same time, a twofold increase in uridine triphosphate (UTP) was measured in liver after intravenously administered UDPG. In contrast, the level of UTP was not increased significantly above control values in tumor. These data suggest the potential use of UDPG to elevate UTP pools in normal tissues in the delayed rescue of cancer chemotherapeutic drugs such as 5-fluorouracil which function as a uridine analogue in these tissues.

Animals↗
PubMed1988

Effect of L-histidinol on the metabolism of 5-fluorouracil in the BALB/c x DBA/8 F1 murine tumor system.

L-Histidinol, a structural analogue of histidine, which transiently inhibits proliferation, can protect cells from the toxic effects of proliferation-dependent chemotherapeutic agents such as 5-fluorouracil (FUra). In the BALB/c x DBA/8 F1 (hereafter called CD8F1) murine tumor system, L-histidinol protected mice from FUra-induced leukopenia, weight loss, and mortality; however, the therapeutic index was not improved since L-histidinol also protected the tumor against the toxic effects of FUra. In order to understand the mechanism of this protection, we examined the effects of L-histidinol on the metabolism of FUra. Results indicate that L-histidinol had no effect on the phosphoribosyl pyrophosphate levels in tumor, the activation of FUra to nucleotides or levels of free 5-fluorodeoxyuridine monophosphate in either tumor or bone marrow. L-Histidinol (7 mg/mouse, every 2 h for 5 doses) reduced RNA and DNA synthesis, as measured by 32P incorporation in vivo, by approximately one-half in tumor, and by 70% in bone marrow. This in turn resulted in reduced incorporation of FUra into RNA in both tumor and bone marrow. At 2 h, 4 h, and 24 h after FUra administration the level of FUra in RNA was 24-37% less in both tumor and bone marrow of mice that received L-histidinol with FUra. Using 32P as a monitor of overall RNA synthesis, the [3H]FUra/32P ratio remained unchanged, suggesting that the reduction of FUra incorporation into RNA was due to decreased RNA synthesis rather than a decrease in the number of FUra molecules per RNA chain. In contrast, L-histidinol had no effect on the in vivo inhibition of thymidylate synthetase by 5-fluorodeoxyuridine monophosphate as measured by the incorporation of [3H]-2'-deoxyuridine into DNA or on the percentages of thymidylate synthetase in the free versus 5-fluorodeoxyuridine monophosphate-bound state. We conclude that L-histidinol reduces FUra toxicity by reducing FUra incorporation into RNA. Since the major mechanism of action in the CD8F1 breast tumor system is the incorporation of FUra into RNA, the reduction in toxicity and antitumor activity observed when L-histidinol is combined with FUra is consistent with the observed reduction in tumor and bone marrow RNA containing incorporated FUra residues.

Animals↗
PubMed1988

Failure of high-dose leucovorin to improve therapy with the maximally tolerated dose of 5-fluorouracil: a murine study with clinical relevance?

Almost all of the completed and ongoing phase III trials of the leucovorin/5-fluorouracil (LV/5-FU) combination have used either a single-agent 5-FU control arm in which the 5-FU was administered in a different schedule from the LV/5-FU arm or one in which the 5-FU was not at the maximally tolerated dose (MTD). Because both dose intensity and scheduling are known to affect drug activity, the LV/5-FU combination was evaluated in the preclinical CD8F1 murine model of advanced first-passage spontaneous breast tumors using the same dose (at MTD) and schedule for 5-FU alone and in the LV/5-FU combination arm. Overall, therapy with 5-FU at MTD was not improved by LV. Further, although the activity of 5-FU doses lower than the MTD could be increased by LV, the therapeutic result was comparable to that of single-agent 5-FU at MTD. In an evaluation with other modulators of 5-FU (e.g., uridine, PALA, methotrexate), therapy with various modulated 5-FU combinations at their MTD was not improved with LV. In conclusion, although LV can enhance the cytotoxicity of 5-FU in these in vivo preclinical studies, it does not confer enhanced selectivity to 5-FU, a conclusion at odds with many present clinical reports. Whether or not these murine findings have clinical relevance can be determined only by clinical trials designed with the MTD of 5-FU alone in the control arm, the MTD of 5-FU (or as close as tolerated) in the LV/5-FU arm, and identical schedules in both arms.

Animals↗
PubMed1988

Chemotherapeutic evaluation using clinical criteria in spontaneous, autochthonous murine breast tumors.

Six drugs, three of which are considered to be active against human breast cancer [melphalan (PAM), cyclophosphamide (CTX), and 5-fluorouracil (FUra)] and three of which have failed to demonstrate activity against human breast cancer [N-phosphonacetyl-L-aspartate (PALA), cytarabine (ara-C), and 6-thioguanine (TG)], were tested at optimal weekly doses in (BALB/-cfC3H X DBA/8)F1 (CD8F1) mice bearing spontaneous, autochthonous breast tumors averaging 300 mg. When treatment was evaluated by laboratory criteria (i.e., tumor growth inhibition in comparison to vehicle-treated, size-matched controls), all six of the drugs tested were judged to be active. However, when the criteria for positive drug activity consisted of the attainment of tumor regressions of greater than or equal to 50% in greater than or equal to 20% of the treated individuals (i.e., analogous to clinical criteria), only the three drugs that are known to be active against human breast cancer (PAM, CTX, and FUra) were judged active against the spontaneous murine breast tumors. PALA, ara-C, and TG failed to demonstrate regressing activity against the spontaneous murine breast tumors. With a caveat concerning the limited spectrum of drugs evaluated in this study, it can be concluded that the CD8F1 breast tumor model demonstrated 100% correlation with human breast cancer in terms of both positive and negative drug sensitivity when the criteria for evaluation were parallel.

Animals↗
PubMed1988

Pressor and intestinal vascular bed responses to vasopressin after cholinergic blockade.

Superior mesenteric arterial flow, aortic blood pressure, and heart rate were recorded, and plasma arginine vasopressin (AVP) concentrations were measured in conscious unrestrained cats during intravenous infusions of AVP (0.1-8.1 mU.kg-1. min-1). Responses to AVP were studied when autonomic nervous system (ANS) function remained intact and when the cholinergic limb of the system had been antagonized by methscopolamine nitrate (0.5 mg/kg) or by pirenzepine (60 micrograms/kg). Elevations in the circulating levels of AVP to approximately 30 and 600 fmol/ml in cats with intact ANS function were associated with decreases in superior mesenteric arterial conductance (SMAC, ml.min-1.kg-1.mmHg-1) of approximately 9 and 50%. The relationship between the dose of AVP and the decreases in SMAC for methscopolamine-treated cats was displaced slightly but significantly to the left of that for intact cats. The relationship between the dose of AVP and the increases in arterial pressure for methscopolamine-treated cats was also significantly displaced to the left of that for intact cats; however, the magnitude of the displacement was much greater than that for the dose-conductance relationship. In contrast to the findings with methscopolamine, pirenzepine did not significantly influence either the dose-conductance or dose-blood pressure response curves. These results are consistent with three conclusions. First, physiologically (less than 30 fmol/ml) and pathophysiologically (less than 600 fmol/ml) relevant concentrations of AVP are capable of inducing intestinal vasoconstriction, even in the presence of intact autonomic function. Second, the cholinergic limb of the autonomic nervous system plays a major role in buffering the vasopressor effects of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Failure of L-histidinol to improve the therapeutic efficiency of 5-fluorouracil against murine breast tumors.

It has been reported that L-histidinol, a structural analogue of the essential amino acid L-histidine, can transiently inhibit proliferative cycling in cells with normal phenotype while allowing continued cell cycle transit in tumor cells. Thus, in the presence of L-histidinol, the toxicity of a proliferation-dependent drug such as 5-fluorouracil (FUra) was found to be reduced in normal tissue cells of the DBA/2J mouse, but not in L1210 leukemia cells in the same mouse. Because of the potential clinical significance of this approach to reduce chemotherapy-associated host toxicity, we evaluated the L-histidinol-FUra combination in a nonleukemic, solid murine tumor model, the BALB/c X DBA/8 F1 (hereafter called CD8F1) breast tumor. The results of these studies indicate that the administration of L-histidinol can protect the CD8F1 mouse from FUra-associated leukopenia, body weight loss, and ultimately, from mortality. However, in contrast to results reported in the L1210 leukemic system, L-histidinol also reduced the cytotoxic activity of FUra against CD8F1 breast tumors. Therefore, although the dose of FUra that could be administered with safety was higher in mice receiving L-histidinol, the therapeutic results of the combination of FUra and L-histidinol were not superior to those obtained with FUra alone at a lower dose.

Animals↗
PubMed1987

Sensitivity of intestinal resistance vessels to vasopressin after ganglionic blockade in the conscious cat.

Superior mesenteric arterial flow, arterial pressure, and heart rate were recorded, and plasma arginine-vasopressin (AVP) concentration was measured, during intravenous infusions of AVP (0.1-8.1 mU X kg-1 X min-1) in conscious unrestrained cats under two experimental situations--when autonomic function remained intact and, on other days, when it had been impaired by pretreatment of the animals with the ganglionic blocking agent pentolinium tartrate (2.5 mg X kg-1 and 0.125 mg X kg-1 X min-1). The dose-related increases in the plasma concentrations of AVP attained during the infusions of the peptide were similar under the two experimental situations. The curve expressing the relationship between the dose of AVP and the decrease in superior mesenteric arterial conductance (ml X min-1 X kg-1 X mm Hg-1) for when ganglia were blocked was similar to the curve for when autonomic function remained intact. Elevations in the circulating levels of the peptide within the physiological range (less than 30 fmol X ml-1) were associated with significant decreases in conductance, both when ganglia were blocked and when they were intact. In contrast to conductance, the curve expressing the relationship between the dose of AVP and the increase in arterial pressure for when ganglia were blocked was displaced markedly to the left when compared with the curve for when reflexes remained intact, even though the effect of ganglion blockade on pressor responses did not reach statistical significance with the two lowest doses of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Prostatic ultrasonography: applicability in a small hospital.

This paper reports the results of a prospective study undertaken to assess the applicability of prostatic ultrasonography in a small community hospital, and to determine the accuracy and technical feasibility of sonographic imaging using contact scanning technique.

Evaluation Studies as Topic↗
PubMed1986

Plasma levels of a viral protein during adjuvant treatment: reflection of murine mammary tumor status and therapeutic effect.

The mouse mammary tumor and its associated virus, mouse mammary tumor virus, were chosen to test the possibility of using plasma levels of a Mr 52,000 viral glycoprotein (gp52) as a means for monitoring changes in tumor status during surgical adjuvant cyclophosphamide:doxorubicin (Adriamycin):5-fluorouracil treatment. Analysis of tumor recurrence and plasma gp52 concentrations during the postoperative period demonstrated that both parameters were significantly decreased in the group receiving cyclophosphamide:doxorubicin:5-fluorouracil treatment. This observation suggests that plasma gp52 levels may be a useful alternative measure of therapeutic effect during surgical adjuvant treatment. A retrospective analysis of gp52 plasma levels and tumor status of individuals during treatment has revealed the following associations. (a) An early sharp postsurgical elevation in plasma gp52 level was associated with subsequent death of treated animals. (b) Maintenance of postsurgical gp52 levels at a low level (less than or equal to 4.2 ng/ml) during and after treatment was characteristic of all tumor-free survivors. (c) A gradual rise in plasma gp52 level accompanied CAF-delayed tumor recurrence. gp52 levels increased in all treated animals 2 wk prior to detectable tumor regrowths, resulting in a statistically significant increase in mean gp52 level (2.2 to 5.4 ng/ml). However, the magnitude of this increase was small for the majority of animals with tumor regrowths, and greater, more definitive elevations in plasma gp52 levels were only detected at the time of frank tumor recurrence. In addition, comparisons of early mean gp52 levels (8 to 10 days after surgery) for controls and for animals receiving various forms of alternative treatment have indicated that differences in gp52 levels reflect subsequent differences in recurrence rates. The present data, obtained during surgical adjuvant treatment of BALB/c X DBA/8 F1 mice and viewed in a retrospective fashion, demonstrate that plasma gp52 concentrations reflected therapeutic effects.

Animals↗
PubMed1986

Role of murine tumor models in cancer treatment research.

Two major factors have contributed to a widely held disenchantment with murine tumor models for drug screening in cancer research: (a) the higher costs of these models in comparison to studies performed with tumor cells in vitro; and (b) the perception that these models have failed to demonstrate satisfactory correlation of chemosensitivity with analogous human tumor types; i.e., murine tumors generally have proved to be sensitive to many more agents than are found to be active in the clinic. The perceived failure of the murine models is discussed with particular reference to the difference in criteria used for evaluating drug sensitivity in murine tumor models versus clinical trials, and we conclude that the perception about murine models is not tenable in light of present information. The very important role of murine tumor models in optimizing dosage and administration schedules and, most importantly, in the development of a new drug to its most useful potential in combination chemotherapy is discussed. The value of this in vivo methodology is stressed.

Animals↗
PubMed1985

Decreased host toxicity in vivo during chronic treatment with 5-flourouracil.

Chronic weekly administration of FUra to CD8F1 female mice bearing spontaneous mammary tumors produced body weight loss during the first 2 weeks of treatment, which became less severe during subsequent weeks of therapy. To our knowledge, the development of such a decrease in FUra toxicity in vivo during chronic treatment with the drug has not been described previously, and a study of this phenomenon was therefore undertaken in tumor-free CD8F1 female mice. Weekly administration of FUra at 85 mg/kg resulted in toxicity expressed in body weight loss and in depressed peripheral WBC levels; however, the magnitude of these toxic effects decreased significantly by the 5th week of treatment. Pretreatment of normal mice with FUra for 7 weeks resulted in a dose-related shift in the LD50 of FUra administered as a subsequent challenge. Compared with an LD50 of 240 mg/kg for FUra in normal mice, the LD50 in mice pretreated with FUra at 50 or 85 mg/kg per week was found to be significantly elevated to 370 and 460 mg/kg, respectively. Pretreatment with FUra at 85 mg/kg for 7 weeks did not alter the activity of the enzymes responsible for the activation of FUra, namely uridine kinase or orotate phosphoribosyltransferase, in the intestinal epithelium or bone marrow, but it did decrease the 24-h urinary excretion of intact [3H]FUra by almost 40% (P less than 0.01). In addition, the FUra pretreatment schedule resulted in a 31% (P = 0.14) increase in the activity of dihydrouracil dehydrogenase in the liver. These results suggest that increased degradation of FUra can be induced by chronic treatment with the drug. Finally, knowledge of the development of increased drug catabolism was used to increase the therapeutic effectiveness of FUra by its incorporation into an increasing-dose regimen. Mice bearing 24-h transplants of the murine breast tumor were treated with a constant dose of FUra for 12 weeks or with a dose that was increased, after 7 weeks, to a dose normally causing a high degree of drug-related mortality. The group receiving the incremented FUra dose had a significantly slower tumor growth rate without an increase in drug-related toxicity. These results are discussed in light of their obvious clinical implications.

Animals↗
PubMed1985

Modulation of chemotherapeutic drug activity with polyribonucleotides or with interferon.

Mouse interferon, or human hybrid recombinant interferon alpha A/D, administered during the 2 day period following the administration of a toxic dose of 5-fluorouracil (FUra), yielded significant protection from body weight loss, leukopenia, and mortality in Balb/c X DBA/8 F1 mice. Protection against FUra-toxicity also was observed when the interferon inducer polyinosinic-polycytidylic acid [poly(I,C)] was administered with FUra. Since it is known that nonproliferating cells exhibit diminished sensitivity to FUra as compared with proliferating cells, it appears likely that the decreased toxicity seen in these experiments can be ascribed to the antiproliferative action of interferon on normal tissues in the mouse which are sensitive to the action of FUra. When poly(I,C) and FUra were coadministered to mice bearing colon tumor 26, the tolerated dose of FUra was increased significantly, and this resulted in significantly increased antitumor activity. These results indicate that differential cytokinetic modulation with interferon, or possibly with other known antiproliferative agents, may provide a new approach for improving clinical results in cancer therapy with available drugs.

Animals↗