Search PubMed⌕ Search

Biomedical subjects

D S Martin

Publications and source records attributed to D S Martin.

At least 181 records · Page 10Linked to original sources
PubMed1981

Quantitation of viral antigens released into plasma and culture fluids by murine mammary tumor cells.

Radioimmunoassay capable of measuring mouse mammary tumor virus (MMTV) 52,000 M.W. envelope glycoprotein (gp52) and 27,000 M.W. protein (p27) have been used to quantitatively compare plasma concentrations of these viral antigens in mice bearing spontaneous mammary tumors. Although gp52 was detected in the plasma of all tumor-bearing mice tested, p27 was detected in only a portion of tumor-bearing animals. In p27-positive animals, gp52 was detected in higher concentrations than p27. These findings demonstrate that gp52 has preferential utility as a plasma marker for the presence of mammary tumors in MMTV-infected hybrid (BALB/c x DBA/8 F1), Paris RIII, and C3H/HeJ mice. In addition, cultures of MMTV-producing cells [GR-MMTV and MMTV(C3H)Fel I] were used as models to study the release of viral antigens in the absence of serum antibody or additional host factors. Comparisons of extracellular soluble and particulate antigen concentrations demonstrated that gp52 and p27 were present in substantially higher concentrations as soluble than virion-associated antigens. The mean ratio of non-virion-associated gp52 to virion-associated gp52 was 12.5:1 for GR-MMTV cells and 37.3:1 for MMTV(C3H)Fel I cells. The marked stability of MMTV in culture fluids suggested that virion breakdown was not responsible for the accumulation of soluble viral antigens in culture. The information obtained suggests that abundant virus-free antigens may be of greater use than virion-associated antigens as a source of viral antigen to evaluate mammary tumor status.

Adenocarcinoma↗
PubMed1981

Modulation of 5-FU action by thymidine in murine and human tumors.

The biochemical basis of, and preclinical experience with, combined chemotherapy with thymidine and 5-FU are reviewed. Phase I trial and clinical pharmacologic evaluation of a monthly schedule of thymidine and 5-FU showed marked increase in the biologic activity of 5-FU. Both toxic and antitumor effects were observed. Myelosuppression was the dose-limiting side effect. The central nervous system toxicity of 5-FU appeared increased; gastrointestinal toxicity was not. The available data do not permit an assessment of whether the therapeutic index of 5-FU has been altered by combination with thymidine. The basis for the observed increase in potency of 5-FU appears to be a thymine-induced marked slowing in its catabolism that results in a prolonged plasma half-life for 5-FU and an increased cellular exposure to the drug.

Animals↗
PubMed1980

An overview of thymidine.

This review summarizes a body of information suggesting that proper metabolic modulation with certain metabolites can sensitize tumor cells to anti-metabolites, and others can de-sensitize (i.e. protect) normal cells from the toxicity of anti-metabolites. This new approach offers the possibility of increasing the selectivity of drug therapy, with the promise of a real advance in cancer chemotherapy. The metabolite thymidine (TdR), long used as a cell synchronizing agent, is known to exert this effect in vitro by metabolic modulation of a number of enzymes in the salvage pathway to DNA synthesis. Against this biochemical background, in vivo effects of TdR employed as an agent for cancer therapy are reviewed as follows: 1) TdR alone, and in combination with, 2) Methotrexate (MTX), or 3) 5-Fluorouracil (FU), or 4) Cytosine arabinoside (ara-C). TdR is shown in all instances either to protect against host toxicity (eg. MTX), or to potentiate the anti-tumor effect (eg. FU and ara-C). Findings are also presented that a sequential schedule of MTX prior to TdR prior to FU is important for the optimal therapeutic activity of these drugs. The biochemical basis for the MTX leads to FU augmentation is reportedly due to increased activation of FU by MTX (acting indirectely). On the basis of this biochemical insight, a completely different chemotherapeutic agent methyl-mercaptopurine raboside (MMPR) was substituted for MTX, resulting in a dramatic potentiation of anticancer activity. Metabolic modulation with still other metabolites (UR) and a hormone (testosterone) was demonstrated to protect from host toxicity due to certain anti-cancer agents without offsetting anti-tumor activity. The ability to prevent leukopenia by these means was particularly impressive. Clinical trials have been initiated with TdR alone, TdR + MTX, and TdR + FU; the available clinical data are summarized.

Animals↗
PubMed1980

Combination clinical trials with thymidine and fluorouracil: a phase I and clinical pharmacologic evaluation.

Phase I observations of combined therapy with thymidine (TdR) and 5-fluorouracil (FU) have demonstrated that when TdR is administered by rapid infusion at a dose of 7.5 or 15g and FU is given by bolus injection 60 minutes after the start of the TdR dose, the biologic activity of Fu is increased five- to eight-fold. The observed toxicity is primarily hematopoietic: 15g TdR and 7.5 or 10mg/kg FU produced median white blood count nadirs of 2,600 on day 16 and platelet count nadirs of 150,000 on day 14. The combined therapy produced two partial remissions in 18 patients with colon cancer, 17 of which had experienced progression of disease on FU containing regimens. Partial remissions were also obtained in two heavily pretreated patients with ovarian cancer and diffuse, poorly differentiated lymphocytic lymphoma. Plasma analyses for TdR and FU and their metabolic products by high pressure liquid chromatography have demonstrated a marked elevation and prolongation of FU levels. The beta phase T 1/2 for 7.5mg/kg FU were: FU alone 6 minutes, 7.5g TdR + FU 135 minutes, 15g TdR + FU 188 minutes, and TdR 45g + FU 190 minutes. The addition of TdR all but eliminated oxidative metabolism of FU; renal clearance became the primary detoxification route. Thymidine levels exceeded 10(-3)M; the beta phase T 1/2 of TdR varied with the administered dose: 3gTdR, 7 minutes; 7.5g TdR, 24 minutes; 15g TdR, 52 minutes; and 45g TdR, 98 minutes.

Adult↗
PubMed1980

The prevalence of obesity and thinness in children from a lower socioeconomic population receiving comprehensive health care.

The relative body weights of 1830 children from low-income families ranging in age from 2 months to 18 years were calculated using the weight-for-length index (WLI). The effects of age, sex and race on WLI were tested with a 3-way analysis of variance test. A significant age and race interaction was found for the whole sample, as well as significant age and sex interaction for blacks only. Additional analysis revealed that most of the variance in WLI could be explained by weight variations in black females. When the children were classified as obese, overweight, and thin basedon their WLI scores, black males were found to have the lowest prevalence of obesity followed by slightly higher values for the other groups. When overweight and obese children were combined into one group, black females had the highest prevalence of overweight-obese children followed by white males, black males, and white females. In contrast, white females had the highest prevalence of thinness, followed by white males, black females, and black males. Additional analysis suggested that there are important social and/or environmental factors within this particular socioeconomic group that are interacting with biological processes to influence the prevalence of obesity and thinness within each age group.

Age Factors↗
PubMed1980

Protection by testosterone from fluorouracil-induced toxicity without loss of anticancer acitvity against autochthonous murine breast tumors.

The present paper describes the specific amelioration of 5-flourouracil (FUra)-induced host toxicity (manifest in body weight loss, leukopenia, and mortality) by testosterone in the spontaneous, autochthonous CD8F1 (BALB/c x DBA/8F1) murine breast tumor model. Administration of testosterone did not affect the growth rate of these hormone-independent tumors, and, most importantly the antitumor activity of FUra was not reduced in testosterone-treated mice. Therefore, the net result of treatment with the combination of FUra and testosterone was an increase in the selective antitumor specificity of FUra.

Animals↗
PubMed1980

Clinical pharmacologic effects of thymidine plus 5-FU.

Ten patients with advanced cancer were given 24 courses of thymidine (TdR) plus 5-FU. In the initial part of the study, TdR was given by continuous infusion at a dose of 8 g/m2/24 hrs x 5 days, and 5-FU was given as an iv bolus daily x 5. During the continuous TdR infusion, TdR serum levels ranged from 10(-6) to 10(-5) M, and thymine serum levels ranged from 10(-5) to 10(-4) M. 5-FU serum decay on Day 1 was rapid, and serum decay on Day 5 was slightly prolonged in two of three patients studied. The optimal dose of 5-FU with continuous infusion of TdR seemed to be between 200 and 400 mg/m2 daily x 5 in heavily pretreated patients. In the second part of the study, rapid infusion of TdR at a dose of 8 g/m2/2 1/2 hrs followed by 5-FU resulted in markedly prolonged 5-FU serum decay (initial serum half-life, approximately 240 mins) and definite increase in clinical toxicity. The dose-limiting toxic effect of both schedules was myelosuppression. Administration of TdR in one tenth of the initial infusion time resulted in a nearly 100-fold increase in peak TdR levels. Thymine was the major metabolite of TdR. 5-FU did not influence TdR blood levels. The protracted 5-FU serum decay appears to account at least in part for the increased toxicity of 5-FU when administered following TdR.

Adult↗
PubMed1978

Crystalline enzyme.substrate complexes of asparate aminotransferase.

Crystalline complexes of cytoplasmic aspartate aminotransferase of pig heart with the substrates L-glutamate and L-aspartate, and with other amino acids, have been prepared and polarized light absorption spectra have been measured. Striking differences in the directions of polarization of the absorption bands are seen. A complete half-transamination of pyridoxal phosphate to pyridoxamine phosphate by aspartate or by cysteine sulfinate can be demonstrated in the crystal as can the accumulation of a quinonoid intermediate with erythro-beta-hydroxyaspartate. X-ray diffraction studies show that the crystals with erythro-beta-hydroxyaspartate and alpha-methylaspartate are isomorphous with those of both alpha and beta subforms of the native enzyme.

Amino Acids↗
PubMed1978

Antitumor tests of amygdalin in spontaneous animal tumor systems.

In a series of 6 experiments with CD8F1 mice with spontaneous mammary adenocarcinomas Sugiura noted by macrovisual observation with some histology an overall average of 21% of mice with lung metastases when treated with 1,000--2,000 mg/kg/day of amygdalin compared with 90% of the control mice. The significance attributed to those early observations is seriously challenged by the negative findings of 3 independent investigators, by 2 out of 3 negative cooperative experiments in which Sugiura participated, and particularly by the blind experiment in which he and others under blind readings found no anticancer activity. Treatment of Swiss albino mice showed no destructive effect upon their spontaneous mammary adenocarcinomas. Of the treated mice, 22% were found by macrovisual observation to have lung metastases while 91% were noted among the controls. The results are subject to questions raised in the discussion. Amygdalin at 2,000 mg/kg/day was ineffective both in treating and preventing the development of spontaneous leukemia in AKR mice. At 1,000 mg/kg/day it was not found effective in preventing or significantly delaying the development of spontaneous mammary tumors in CD8F1 mice. In summary, we do not have evidence to support taking amygdalin to clinical trial, although other considerations may require that one be conducted.

Adenocarcinoma↗
PubMed1978

Therapeutic activity of maleic anhydride-vinyl ether copolymers against spontaneous, autochthonous murine mammary tumors.

We have tested a series of five maleic anhydride-vinyl ether copolymers of varying molecular weight for antitumor activity against spontaneous, autochthonous murine breast tumors (average initial tumor weight, approximately 200 mg). Four of the five compounds demonstrated statistically significant inhibition of tumor growth at nontoxic doses. (The fifth compound demonstrated antitumor activity only at toxic doses). To our knowledge, this is the first report of significant activity in a spontaneous solid tumor system in a truly therapeutic setting (ie, with systemic administration only after the autochthonous tumors are clinically evident) with immunologic treatment alone.

Animals↗
PubMed1977

Plasma levels of a viral protein as a diagnostic signal for the presence of mammary tumor: the effect of tumor removal.

We have previously shown (1, 2) that mice with mammary tumors can always be identified by their very high plasma levels of gp52, a 52,000 mol wt glycoprotein of the mouse mammary tumor virus (MMTV). The present investigation demostrates that the tumor is the principal source of the plasma gp52 since surgical excision is invariably followed in the first 9 days by a sharp decreasing (10-100-fold) of the gp52 levels. Control animals in which the tumors were left in place by a "sham" surgical procedure maintained their high level of gp52, which continued to increase as the disease progressed. The behavior of the gp52 after surgical removal suggests that gp52 plasma concentrations are diagnostically and prognostically informative, as indicated by the following finding: (a) All tumor recurrences were correctly diagnosed by increases in gp52 levels, and some were detected 4-7 days before they were found by palpation. (b) Tumor regrowths were accompanied by continued increases in plasma gp52 concentrations at rates that usually matched the speed of tumor development. (c) The only animals that remained tumor free at the termination of the experiment were those that maintained their gp52 levels at or below 15 ng/ml. (d) The probability of a tumor-free animal relapsing within 2 wk is much higher if its gp52 level is above the mean. (e) More remarkably, the plasma levels of gp52 at the time of surgery are superior to the size of the tumors removed as prognostic indicators of eventual surgical "cures". The availability of a specific and sensitive systemic measure of disease status should augment the usefulness of the murine mammary tumor model by catalyzing a more rapid acquisition of information on the therapeutic effectiveness of the new and varied drug combinations being tested for adjuvant chemotherapy.

Animals↗
PubMed1977

Comparison of adjuvant chemotherapeutic activity against primary and metastatic spontaneous murine tumors.

Metastatic tumor incidence in BALB/C X DBA/8F1 female mice was examined in the presence and absence of adjuvant chemotherapy. Following surgical removal of spontaneous mammary adenocarcinomas, phenylalanine mustard, adriamycin, and 5-fluorouracil (PAF) were administered at 4, 2, and 50 mg/kg, respectively, once a week for six injections. Recurring tumors and new tumors developing in other breasts over the next 6 months were noted and surgically removed to allow time for originally undetectable pulmonary metastases to develop or to regress completely. This regimen of PAF significantly decreased original tumor recurrences from 58% in controls to 36% in treated mice. New tumor development also was significantly reduced during the 5 weeks of PAF therapy and for 8 weeks thereafter. However, the incidence of pulmonary metastasis was unaffected by the chemotherapy, being 42% in controls and 37% in PAF-treated mice. About 30% of these metastases would have been undetectable at the time of original surgery. The findings stress the importance of developing agents and/or schedules that will specifically affect metastatic cells when administered early to minimal numbers of tumor cells. This system represents a stringent clinimimetic model for evaluating adjuvant chemotherapy in this regard.

Adenocarcinoma↗
PubMed1976

Plasma levels of a viral protein as a diagnostic signal for the presence of tumor : the murine mammary tumor model.

We used the mouse mammary tumor and its associated virus (murine mammary tumor virus) to examine the possibility of using plasma levels of a viral protein (gp52, the glycoprotein of 52,000 molecular weight) as a diagnostic indicator of the presence of a solid tumor. The following features have emerged from our studies: (a) tumor-bearing animals show markedly elevated (100-1000 ng/ml) plasma levels of gp52 and the mean concentration increases with tumor size; (b) mammary tumor tissues located outside the mammary gland are also detected by the elevated plasma gp52; (c) low (2-10 ng/ml) plasma levels of gp52 are found in tumor-free mice, whether they are derived from strains characterized by high or low frequencies of spontaneous mammary tumors; (d) tumor-free lactating females exhibit the normally low levels of plasma gp52 despite the fact that their milk contains an average of 20,000 ng/ml of this antigen; (e) thus, high levels of plasma gp52 are found only in the presence of tumor and are not induced by either predisposition for the disease or by normal production of the antigen during lactation; (f) the circulatory clearance time of gp52 is sufficiently rapid to require continued replenishment to maintain the high levels observed in tumor-bearing animals, a feature implying that the gp52 concentration can be a responsive parameter of disease status. The information obtained suggests that plasma gp52 is a potentially useful and specific systemic indicator of the presence and extent of murine mammary neoplasia.

Animals↗
PubMed1975

Development and inhibition of cytotoxic antibody against spontaneous murine breast cancer.

Increased cytolytic activity of mouse complement as a result of modified reaction conditions described permitted the detection of tumor-specific cytotoxic antibody in high dilutions of sera (1:100--1:000) from mice carrying spontaneously occuring autochthonous breast tumors, or primary syngeneic transplants of such tumors. However, these same sera failed to demonstrate cytotoxic antibody activity at low dilution (i.e., 1:10). Such a pattern of reactivity suggested the presence of an inhibitor of cytotoxic antibody in high concentrations of serum from tumor-bearing mice. Sequential measurements subsequent to primary tumor implantation revealed that, although the time of appearance of this inhibitor varied from tumor to tumor, it always became detectable simultaneously with significant levels of lymphocyte-blocking activity. Also like lymphocyte-blocking activity, the inhibitor of cytotoxic antibody disappeared following surgical tumor removal. In addition, the inhibitor of cytotoxic antibody activity was shown to operate through a competitive antigen-binding and blocking mechanism. This data suggests the possibility that a single serum moiety may be responsible for the efferent blocking of both the cellular and the humoral components of the immune tumor rejection response.

Animals↗