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Biomedical subjects

D S Martin

Publications and source records attributed to D S Martin.

At least 163 records · Page 9Linked to original sources
PubMed1985

Coordinate inhibition of plasminogen activator and tumor growth by hydrocortisone in mouse mammary carcinoma.

A body of evidence has suggested that hormones which modulate plasminogen activator production by cultured tumor explants in vitro may have a qualitatively comparable effect on the growth of the same tumors in vivo. As a test of this correlation and to explore its potential for predicting the in vivo response of tumors to hormones, we have studied here the effect of hydrocortisone on the growth of primary and first generation transplants of mouse mammary tumor virus-determined mammary tumors in BALB/c X DBA/8 F1 (hereafter called CD8F1) mice; hydrocortisone had been found previously to inhibit plasminogen activator production by explants of these tumors. The results were: (a) hydrocortisone reversibly blocked the growth of palpable primary tumors; growth resumed at control rates following withdrawal of exogenous hormone; (b) hydrocortisone inhibited the growth of first-generation tumor transplants when administered either before or after the appearance of palpable tumors; (c) pretreatment with hydrocortisone both delayed the appearance of primary tumors and greatly reduced tumor incidence in susceptible mice; a substantial part of the decrease in tumor incidence was apparently irreversible; (d) hydrocortisone reduction of tumor growth was accompanied by inhibition of tumor plasminogen activator content, and these effects displayed a similar dose dependence (enzyme content of tumor lysates was measured by the 125I-fibrin plate assay); the enzyme present in control and hormone-treated tumors was predominantly of the urokinase type. These findings suggest that plasminogen activator production and mammary tumor growth in CD8F1 mice are coordinately regulated and thus encourage the view that plasminogen activator might be useful as an in vitro marker for predicting the in vivo response of tumors to hormones.

Animals↗
PubMed1985

Therapeutic effect reflected by plasma levels of a viral protein during combination chemotherapeutic treatment of mammary tumor-bearing mice.

Plasma concentrations of gp52, a Mr 52,000 glycoprotein of the mouse mammary tumor virus, have been measured during cyclophosphamide, doxorubicin (adriamycin) and 5-fluorouracil (CAF) treatment of mammary tumor-bearing CD8F1 mice. The value of plasma concentrations of gp52 as an indicator of CAF-mediated changes in tumor status was supported by each of the following findings: (a) CAF treatment did not interfere with the detection of elevated viral antigen levels in the plasma of tumor-bearing mice; (b) at 9-11 days after initiation of treatment, a significantly lower mean gp52 level, observed in the group of CAF-treated mice, provided definitive evidence of therapeutic effect; and (c) serial determinations of plasma gp52 levels in individual mice before, during, and after treatment provided a relative measure of therapeutic effect for each individual that was a reflection of corresponding changes in tumor size. Changes in viral antigen levels (i.e., decrease or increase) reflected inhibited tumor growth, as well as tumor regression. These findings demonstrate that plasma concentrations of gp52 can be utilized to provide an alternative measure of therapeutic effect in CAF-treated mice bearing significant tumor loads.

Animals↗
PubMed1984

Phase I evaluation of a biochemically designed combination: PALA, thymidine, and 5-FU.

Fifteen patients with advanced solid tumors participated in a phase I study of a biochemically designed combination chemotherapy program which employed PALA and thymidine (TdR) with 5-FU. PALA (250-2000 mg/m2) was given 24 hours before a 90-minute iv infusion of TdR (45 g). 5-FU (100-150 mg/m2) was given as a rapid iv injection 30 minutes after beginning the TdR infusion. This three-drug treatment was repeated once weekly for 3 weeks. Neurotoxicity, manifested as dizziness, lethargy, and confusion, was dose-limiting. Myelosuppression was noted at all dose levels, as was mild to moderate mucositis and diarrhea. Further clinical evaluation of this combination does not appear to be warranted.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Incorporation of 5-fluorouracil into murine bone marrow DNA in vivo.

Although 5-fluorouracil (FUra) is readily incorporated into RNA, the possibility of its being incorporated into DNA in substantial amounts has only recently been recognized. Examination of nucleic acids prepared from tumor-bearing BALB/c X DBA/8 F1 mice labeled with [3H]FUra in vivo revealed very little alkali-stable, acid-precipitable radioactivity in tumor and only small amounts in intestine. However, substantial amounts were detected in bone marrow. Pretreatment of mice with low-dose thymidine (500 mg/kg) increased the incorporation of FUra into RNA but did not change the amount incorporated into alkali-stable material. The net result was a reduction in the fraction of the total in an alkali-stable form. Formation of DNA containing FUra residues is substantially reduced if the mice receive very high doses of thymidine along with the labeled FUra, presumably through competition from an expanded deoxythymidine triphosphate pool. Bone marrow nucleic acids labeled with 32P and [3H]FUra were analyzed by cesium sulfate gradients. Two distinct peaks of tritium radioactivity were observed that band with 32P radioactivity at the densities of RNA and DNA. Pretreatment with alkali destroyed the (32P/3H)RNA peak, but not the DNA peak. Cesium sulfate-purified DNA containing FUra residues was digested with pancreatic DNase and venom phosphodiesterase. The resulting nucleotides were analyzed by high-pressure liquid chromatography. The majority of the radioactivity cochromatographed with 5-fluorodeoxyuridine monophosphate marker. No radioactivity was detected in the regions corresponding to fluorouridine monophosphate or deoxyuridine monophosphate, although radioactivity was detected cochromatographing with deoxythymidine monophosphate. After digestion with alkaline phosphatase, the majority of the radioactivity cochromatographed with fluorodeoxyuridine (and some thymidine). These results confirm previous observations of FUra incorporation into DNA of tissue culture cells.

Animals↗
PubMed1983

Modulation of 5-fluorouracil-induced toxicity in mice with interferon or with the interferon inducer, polyinosinic-polycytidylic acid.

Partially purified preparations of mouse interferon, administered during the 2-day period following the administration of a toxic dose of 5-fluorouracil (FUra), yielded significant protection from mortality in BALB/c X DBA/2 F1 mice. Protection against FUra-induced toxicity was also observed when the interferon inducer polyinosinic-polycytidylic acid (poly I X poly C) was administered with FUra. The temporal relationship between the administration of poly I X poly C and FUra was found to be a critical determinant of the intensity of toxic manifestations. In relation to FUra alone, poly I X poly C could enhance (when administered 48 hr before FUra), diminish (when administered together with FUra), or not affect (when administered 48 hr after FUra) the degree of resultant toxicity. Cytofluorometric analysis of the DNA content of bone marrow cells indicated a transient period (about 42 hr) of inhibition of cell cycling following the administration of poly I X poly C, followed by reentry into cycle (between 42 and 66 hr) and a return to normal cycle phase distribution by 90 hr. This disturbance of the kinetic pattern of cell cycling in bone marrow would explain the administration time-dependent variability of the effect of poly I X poly C on FUra toxicity, since FUra is known to be a cell cycle-specific cytotoxic drug. Potential practical application of this observation to the clinical use of FUra in cancer therapy is discussed.

Animals↗
PubMed1983

Therapeutic utility of utilizing low doses of N-(phosphonacetyl)-L-aspartic acid in combination with 5-fluorouracil: a murine study with clinical relevance.

Doses of N-(phosphonacetyl)-L-aspartic acid (PALA) lower than those required for therapeutic activity against the spontaneous murine breast tumor (BALB/c X DBA/8 F1) were found to produce significant depression in uridine triphosphate pools in the tumor. Using such low, nontherapeutic, but biochemically active doses of PALA in combination with 5-fluorouracil (FUra(, it was possible to maintain the dose of FUra at its full maximum tolerated single agent dose. In comparison with the maximum tolerated dose of FUra alone, the combination of FUra plus low-dose PALA produced a significant increase in the level of tumor FUra-containing RNA, only a slight increase in intestinal FUra-containing RNA, and no increase in bone marrow FUra-containing RNA. These biochemical results correlated with the therapeutic findings of significantly increased antitumor activity without an increase in host toxicity. A review of currently reported PALA plus FUra clinical protocols reveals that the experimental parameters which have produced successful therapeutic results in the laboratory (i.e., a low-PALA:high-FUra dosage ratio) have not yet been translated into clinical trial. Final judgment on the clinical efficacy of PALA:FUra combinations must await the results of proposed low-PALA:high-FUra clinical trials.

Animals↗
PubMed1983

Improved therapeutic index with sequential N-phosphonacetyl-L-aspartate plus high-dose methotrexate plus high-dose 5-fluorouracil and appropriate rescue.

Although clinical trials of high-dose methotrexate (MTX) sequenced before 5-fluorouracil (FUra) with leucovorin (LV) rescue apparently have resulted in increased numbers of tumor responses, this increased antitumor activity often has been accompanied with toxicity. The present report describes an attempt to improve therapeutic results with this drug combination by appropriate metabolic modulation in the preclinical BALB/c X DBA/8 F1 murine breast tumor model. A LV rescue schedule consisting of 300 mg/kg administered at 4.5 and 19.5 hr after high-dose MTX (300 mg/kg/week for 3 weeks) prevented MTX toxicity. When FUra was administered 2.5 hr after MTX (with LV rescue), the dose of FUra had to be decreased, and we could not obtain convincing evidence for a differential cytotoxic effect on tumor versus normal host tissue. However, when a delayed uridine rescue schedule was added to protect the host from the toxic activity of FUra, the FUra dose could be increased even in the presence of high-dose MTX, and the therapeutic result was enhanced significantly without an increase in host toxicity. Finally, it was possible to add N-phosphonacetyl-L-aspartate to this drug combination (in the appropriate sequence: N-phosphonacetyl-L-aspartate before high-dose MTX-before high-dose FUra, followed by double rescue with LV and uridine) without producing increased toxicity to yield a significant increase in partial tumor regression rate. The biochemical rationale for the selection and sequence of administration of these agents is discussed.

Animals↗
PubMed1983

Phase I and clinical pharmacological evaluation of biochemical modulation of 5-fluorouracil with N-(phosphonacetyl)-L-aspartic acid.

5-Fluorouracil (FUra) is a clinically useful antineoplastic agent. Preclinical studies suggest that the therapeutic effects of FUra can be enhanced by pretreatment with N-(phosphonacetyl)-L-aspartic acid (PALA), an inhibitor of aspartate transcarbamylase. The objective of treatment with PALA is to increase the activation of FUra by inhibiting the normal pathway of de novo pyrimidine biosynthesis. Theoretically, the optimal dose of PALA should produce effective blockade of this pathway without increasing toxic effects of FUra. Using pyrazofurin-induced orotic aciduria and orotidinuria as a measure of this pathway, it as determined that PALA (250 mg/sq m) is effective in inhibiting total-body pyrimidine synthesis. Sixty-eight adult patients with cancer were treated with combinations of PALA and FUra. High doses of PALA (1 to 2 g/sq m) prevented the use of full dosage of FUra; however, PALA (250 mg/sq m) can be administered 24 hr before FUra (750 mg/sq m) once weekly for at least 3 weeks. The toxicity observed using that combination of doses was mild to moderate myelosuppression, mucositis, diarrhea, nausea, and vomiting. Further clinical studies are warranted.

Adult↗
PubMed1982

High-dose 5-fluorouracil with delayed uridine "rescue" in mice.

Because of the association between the incorporation of 5-fluorouracil (FUra) into RNA and cytotoxicity, uridine was examined for potential selective reduction of host toxicity. Male BALB/c x DBA/2 F1 mice (tumor free or bearing advanced colon tumor 26) were used. Two uridine schedules (each beginning 2 hr after FUra) have been successful: (a) uridine at 800 mg/kg every 2 hr for three doses followed 18 hr later by uridine at 800 mg/kg every 2 hr for four doses; or (b) two doses of uridine at 3500 mg/kg separated by an 18-hr interval. With two doses of uridine at 3500 mg/kg, the 50% lethal dose for a single dose of FUra in tumor-free mice was increased 68% from 190 to 320 mg/kg. White blood cell levels were depressed 67% after a single dose of FUra at 200 mg/kg, whereas white blood cells were depressed by only 39% when the same dose of FUra was followed by uridine rescue. In tumor-bearing mice, uridine rescue reduced FUra-induced host toxicity without significant loss of antitumor activity. Even more striking results were obtained with a combination containing N-(phosphonacetyl)-L-aspartate (200 mg/kg) and 6-methylmercaptopurine riboside (25 mg/kg), administered 24 hr before FUra. In this drug combination, the maximum tolerated dose of FUra is 40 mg/kg on a weekly schedule. With uridine rescue, FUra can be doubled to 80 mg/kg without increasing toxicity, resulting in significantly improved antitumor activity. Examination of the effect of uridine rescue on the incorporation of FUra into RNA and the subsequent recovery from inhibition of DNA synthesis in bone marrow versus tumor revealed that the uridine rescue schedule resulted in relatively faster clearance of FUra from RNA of both tissues but a striking enhancement of the rate of recovery of DNA synthesis only in the bone marrow.

Animals↗
PubMed1981

Cost effective lab service system: better quality medicine at lowered costs.

In this article, the authors describe the Cost Effective Laboratory Service System, a new concept which they explain can reduce hospitalization costs while maintaining or enhancing the quality of medical care. Discussed are the operational features of the system, the development of subsets, prototype trials, and the advantages of and objections to the system.

Cost-Benefit Analysis↗