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Biomedical subjects

D J Hutchison

Publications and source records attributed to D J Hutchison.

At least 19 recordsLinked to original sources
PubMed1978

Antitumor tests of amygdalin in transplantable animal tumor systems.

Except for oral administration, there was no grossly observed toxicity from carefully administered high doses of amygdalin in the experimental systems used. The compound in high doses was ineffective against the DMBA-induced rat mammary carcinoma and the following transplanted experimental tumors: Sarcoma 180, plasma cell tumor LPC-1, leukemia L1210, Mecca lymphosarcoma, Ridgway osteogenic sarcoma, sarcoma T241, mammary carcinoma E0771, Taper liver tumor, Ehrlich carcinoma (solid and ascites), and Walker carcinosarcoma 256. Amygdalin did not noticeably influence the toxicity or impair the efficacy of these chemotherapeutic agents in their respective systems: Cytosine arabinoside, methotrexate, cytoxan, or 5-fluorouracil in L1210; the latter two in LPC-1; 6-mercaptopurine in Ridgway osteogenic sarcoma; estradiol-17beta or 2alpha-methyldihydrotestosterone propionate in the DMBA-induced rat mammary carcinoma.

Amygdalin↗
PubMed1978

Carboxypeptidase displaying differential velocity in hydrolysis of methotrexate, 5-methyltetrahydrofolic acid, and leucovorin.

An enzyme that catalyzes the hydrolysis of folic acid and the antifolate methotrexate nearly 20 times more rapidly than the hydrolysis of 5-methyltetrahydrofolate was extraced from a gram-negative bacterium tentatively identified as a Flavobacterium sp. The enzyme was purified 500-fold and found to have a molecular weight of about 53,000. Apparently a metallo-enzyme, it is inhibited by citrate and ethylenediaminetetraacetic acid (EDTA). Ca2+, Co2+, Mg2+, and Zn2+ reverse inhibition by EDTA, whereas Ca2+ and Zn2+ are weak activators in the absence of EDTA. The enzymatic reaction releases the carboxy-terminal glutamyl moiety of derivatives of pteroyl-mono-L-glutamic acid. Substituents on N5 of the pteridine ring decrease the velocity of hydrolysis. Some non-specificity for the terminal amino acid is expressed. The strikingly different rates of hydrolysis of methotrexate and 5-methyltetrahydrofolate have stimulated interest in this enzyme for its potential clinical value in improving the therapeutic index of methotrexate.

Carboxypeptidases↗
PubMed1977

Microbiologic assays of cancer chemotherapeutic agents.

Among various assay methods available for the study of drug distribution kinetics in cancer chemotherapy, a method that determines the drug in its active form is the most desirable. The microbiologic assay method, with its rapid, simple, and inexpensive procedures, fulfills such a requirement. Besides the two commonly used chemotherapeutic agents, methotrexate and cytosine arabinoside, microbiologic assays are available for other chemotherapeutic agents, such as 6-mercaptopurine, 5-fluorouracil, actinomycin D, adriamycin, and daunorubicin. Assays have been developed for citrovorum factor and 5-methyltetrahydrofolate in the presence of high levels of methotrexate. With the introduction of combination chemotherapy, microbiologic assay methods using resistant mutants, sensitive to a single drug but resistant (either due to mutation or due to culture conditions) to all other drugs involved in the combination, could well be the most efficient for the study of distribution kinetics. Several such assay methods employed in our laboratory are discussed.

Antineoplastic Agents↗
PubMed1977

A microbiologic disc assay for 5-methyltetrahydrofolate in the presence of methotrexate.

High-dose methotrexate-citrovorum factor rescue regimens are used extensively for the treatment of human malignancies. Since the rescue agent citrovorum factor is rapidly converted to 5-methyltetrahydrofolate, it is desirable to follow the distribution kinetics of both of these coenzymes to assess the selective therapeutic effectiveness of the regimen. The assay methods using methotrexate-resistant strains of Lactobacillus casei ATCC 7469 (LC/A), Streptococcus faecium var. durans ATCC 8043 (SF/A), and Pediococcus cerevisiae ATCC 8081 (PC/A) have been developed to determine the concentrations of 5-methyltetrahydrofolate and other folates in the presence of methotrexate. Since LC/A determines the total folates, SF/A deterimines the total folates except 5-methyltetrahydrofolate, and PC/A by our procedure determines only the most stable form of reduced folates, citrovorum factor, the quantitation of both 5-methyltetrahydrofolate and citrovorum factor can very easily be achieved by differential assays. This report describes the determination of as low as 10 ng/ml of 5-methyltetrahydrofolate in the presence of as high as 500 microgram/ml of methotrexate. The assay method described here is currently used in studying the pharmacokinetics of 5-methyltetrahydrofolate in patients with meningeal neoplasms.

Biological Assay↗
PubMed1977

Perilymph penetration of methotrexate in cats.

The perilymph of the inner ear has recently been suggested as a site of frequent leukemic or lymphomatous infiltrates. Experimental evidence supports the existence of barrier mechanisms and explains the attenuated entry of several substances, including chemotherapeutic agents, from either the cerebrospinal fluid or blood into theperilymph. The present study describes the attenuated entry of methotrexate into the perilymph compartment of experimental animals following intrathecal or iv administration.

Animals↗
PubMed1976

Deveopment of resistance to combinations of six antimetabolites in mice with L1210 leukemia.

The development of resistance to combinations of 6-mercaptopurine, 6-thioguanine, 6-methylmercaptopurine riboside, methotrexate, 5-fluorouracil, and cytosine arabinoside was studied in L1210 leukemia through 60 transfer generations. The treatment schedules were either simultaneous or offset. In simultaneous administration, one sixth of the LD10 of each of the six drugs was administered within a few minutes, daily for 6 days. In offset administration, the drugs were given either in the above-listed order or in reversed order, with one drug given each day. In the simultaneous combination treatment protocol 31 transfer generations were necessary to reach partial resistance, but in the two offset combination schedules only five and three generations were needed. The relative rate of development of resistance to the individual drugs was slower in the three combination schedules than in single-drug schedules. Resistance to 6-mercaptopurine and 6-thioguanine was completed after four generations on the offset combination schedules, but only after 28 generations on the simultaneous schedule.

Animals↗
PubMed1976

Radiation-induced murine leukemia ERLD in cell culture.

The lymphoblastic leukemia ERLD, induced by radiation in a C57BL/6 mouse, was established in culture. Three cell lines, ERLD/Y3, ERLD/T ERLD/Two, have been in culture for nearly three years. Their isolation and growth depended upon the presence of 2-mercaptoethanol, glutamine, and asparagine in the medium. The cell lines, except ERLD/T, possess the TL antigen, a characteristic of ERLD and of other murine leukemia cells in vivo and of normal thymus cells of certain mouse strains, but not of C57BL/6. A distinctive submetacentric marker chromosome is also common to ERLD and the derived cell lines. The successful establishment of ERLD in culture provides a malignant thymocyte-related cell system for studies in nutrition and immunobiology.

Animals↗
PubMed1975

Identification of the virions in the in vitro L1210(V) leukemia cell lines by morphological, virological, and immunological techniques.

In vitro L1210 (V) cell lines contained abundant intracytoplasmic A-particles, numerous C-type particles, a small number of B-type particles, and occasional intracisternal A-particles. The intracytoplasmic A-particles were incorporated into both spiked (B-type) and smooth-surfaced (C-type) particles formed at the budding site. Both B-and C-type particles also developed by gradual accululation of neucleooid material. The particles, particularly the C-type, exhibited a wide range of densities. The cells showed strong surface immunofluoresence for both murine mammary tumor virus and Gross murine leukemia virus antigens and variable degrees of cytoplasmic immunoflurescence for the protein antigens (p1 to p6) of Rauscher leukemia virus. The cells, the culture supernatant, and the purified virus each gave positive reactions with murine mammary tumor virus and murine leukemia virus antisera by immunodiffusion. The viral particles failed to infect C57BL, C57BL/6 X DBA/2F1 (hereafter called BD2F1), BALB/c, Af,and RIIIf mice. Howver, the cells were highly tumorigenic in BD1F-1 mice, moderately tumorigenic in BALB/c mice, but not tumorigenic in C57BL, Af, and RIIIf mice.

AKR murine leukemia virus↗