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Biomedical subjects

R K Johnson

Publications and source records attributed to R K Johnson.

At least 253 records · Page 14Linked to original sources
PubMed1976

Antitumor activity of N-(phosphonacetyl)-L-aspartic acid, a transition-state inhibitor of aspartate transcarbamylase.

N-(Phosphonacetyl)-L-aspartate (PALA) is an analog of the transition state for the aspartate transcarbamylase reaction and has been reported previously to be a potent and specific inhibitor of de novo pyrimidine nucleotide biosynthesis. It is now shown that PALA has considerable antitumor activity against certain transplantable tumors in mice. PALA, unlike other antimetabolites, was less effective against ascitic leukemias than against two solid tumors, B16 melanoma and Lewis lung carcinoma. Another solid tumor, Ridgway osteogenic sarcoma, which is sensitivie to many established chemotherapeutic agents, did not respond to PALA. Daily or intermittent treatment with PALA did not significantly increase the life-span of mice bearing i.p. leukemia L1210. The survival time of mice bearing i.p. P388 leukemia was prolonged by PALA treatment by up to 64%. In a number of experiments mice bearing i.p. B16 melanoma survived 77 to 86% longer than did controls when treated with PALA (490 mg/kg) on Days 1, 5, and 9. Lewis lung carcinoma, a tumor refractory to most established antineoplastic agents, was highly sensitive to PALA. Treatment on Days 1, 5, and 9 following s.c. implantation of Lewis lung carcinoma was curative to 50% of the mice. If treatment was delayed until s.c. Lewis lung tumors had reached about 500 mg, PALA neither cured the mice nor produced significant tumor regression. However, extensive delay of tumor growth and prolongation of survival were still observed.

Animals↗
PubMed1976

Comparison of 5-fluorouracil and ftorafur. I. Quantitative and qualitative differences in toxicity to mice.

5-Fluorouracil (5-FU) was compared to ftorafur, a fraudulent nucleoside analog which acts as a depot form of 5-FU, with respect to influence of dosage level and schedule of administration on toxicity in mice. When the drugs were administered daily and the duration of treatment was varied from a single dose to 32 daily treatments, the toxicity of 5-FU proved to be somewhat more than cumulative. On the other hand, the toxicity of ftorafur on daily treatment was less than cumulative. As a single treatment ftorafur was about half as toxic as 5-FU on an mg/kg basis. When the drugs were administered daily for 12 days the LD50 of ftorafur was about sevenfold that of 5-FU. When the drugs were administered as two treatments and the interval between the two treatments was varied from 0 to 14 days, it was found that 5-FU was considerably more toxic at an interval of 2-7 days than when two doses were administered simultaneously. Appreciable recovery of mice from the initial dose of 5-FU did not occur until sometime between 7 and 10 days. Host recovery from ftorafur toxicity was apparent by 2 days. The dose-mortality curves form both drugs were steep. The decreased toxicity with repeated treatment with ftorafur relative to 5-fu was not due to a decrease in the metabolism of ftorafur to 5-FU, which was much more extensive in mice compared to previously reported pharmacokinetic studies in other species. At equitoxic doses on a daily X 5 schedule, 5-FU and ftorafur had similar myelosuppressive activity. Ftorafur was, however, clearly less suppressive to both humoral and cell-mediated immunity than was 5-FU.

Animals↗
PubMed1976

Comparison of 5-fluorouracil and ftorafur. II. Therapeutic response and development of resistance in murine tumors.

The therapeutic activity of ftorafur was compared to that of 5-fluorouracil (5-FU) in a number of tumor systems. The drugs were active against ip L1210 leukemia when administered ip, sc, or orally. Administration every fourth day x 3 proved to be the most effective treatment schedule for both drugs, although significant activity was seen on all treatment schedules tested. Both congeners had activity against sc implanted L1210 leukemia as well as a limited effect on the ic implanted tumor. 5-FU produced greater increases in lifespan of mice bearing L1210 leukemia than did ftorafur. 5-FU was also more effective against ip B16 melanoma and ip Gardner 6C3HED lymphosarcoma. Ftorafur was ineffective in the treatment of mice bearing ip P388 leukemia, a tumor which is quite sensitive to 5-FU. At approximately equimolar doses both drugs produced a persistent inhibition of 2'-deoxyuridine incorporation into DNA of L1210 cells in vivo. Ftorafur produced a greater inhibition of uridine incorporation into RNA than did 5-FU, which may account for the lower therapeutic activity of ftorafur. In combination chemotherapy of L1210 leukemia 5-FU plus ftorafur was no more effective than 5-FU alone, neither of the congeners was synergistic with either adriamycin or actinomycin D, and in combination with methotrexate therapeutic synergism was observed with 5-FU but not with ftorafur. After eight transplant generations of exposure to ftorafur, a subline of L1210 leukemia became totally resistant to ftorafur and simultaneously cross-resistant to 5-FU. Doses of ftorafur and 5-FU which were optimally effective in mice bearing the parental L1210 line were lethal to mice implanted with the ftorafur-resistant subline. When treatment of the resistant subline was discontinued after nine transplant generations of exposure to ftorafur, sensitivity to 5-FU returned after three transplant generations without ftorafur. The subline retained its resistance to ftorafur until eight transplant generations after cessation of ftorafur treatment. Another subline of L1210 leukemia exposed to 5-fU for 20 transplant generations proved to be completely resistant to 5-fu and cross-resistant to ftorafur. The mutual cross-resistance between ftorafur and 5-FU supports the contention that ftorafur acts primarily as a depot form of 5-FU.

Animals↗
PubMed1975

Effects of cyclophosphamide and adriamycin on the healing of surgical wounds in mice.

Administration of therapeutic dose levels of cyclophosphamide as a single dose or as daily treatments for 5 days during the perisurgical period resulted in a significant decrease in the strength of surgical skin wounds in mice as measured 21 days after surgery. Administration of a single dose of 200 mg/kg either at the time of surgery or up to 4 days prior to or after surgery impaired 21-day wound strength, with the most extensive depression observed when the drug was given 1 or 2 days after surgery. Earlier stages of wound healing (day 3 or day 7) were not as sensitive to cyclophosphamide. Adriamycin in the therapeutic dosage range for mice did not significantly impair wound healing. This drug had an effect only at the LD10 dosage level. Combination treatment with cyclophosphamide plus adriamycin at the time of surgery impaired 21-day wound strength to a greater degree than observed with either agent alone, but did not significantly depress wound strength 3 or 7 days after surgery. These studies indicate that dosage level, the time of drug administration relative to surgery, and the time at which wound strength measurements are made are important parameters in determination of the effects of antineoplastic agents on wound healing.

Animals↗
PubMed1975

Erythrocyte volume distribution in normal and abnormal subjects.

Size-frequency distribution curves of erythrocytes were generated with the Coulter Counter in 73 normal subjects and patients. Mean corpuscular volume (MCV) determined by routine calculation and MCV determined by size-frequency distribution were similar in all normal subjects and in patients with a single population of erythrocytes. Some patients with iron-deficiency anemia, folate deficiency, and vitamin B12 deficiency had two discrete erythrocyte populations. Some patients with microcytic anemia were shown to have a population of normocytes in addition to the predominant microcytic population. Reticulocytes and normocytes were identified in two patients recovering from macrocytic anemia. Transfused blood was identified as a separate population in a patient with microcytic anemia. In cases with two erythrocyte populations, the MCV of the principal population, as determined from size-distribution curves, differed from the MCV of the entire erythrocyte pool, as was determined by routine methods. Analysis of sequential erythrocyte size distributions in patients under treatment demonstrated the dynamics of erythrocyte subpopulations. Anisocytosis was quantified and shown to be associated frequently with hospitalized patients.

Adenocarcinoma↗
PubMed1975

The fascia of the distal phalanx.

The anatomy of the distal phalanx of the human finger was studied in preserved and fresh specimens and the fascia was related to associated structures as a mechanism for prehension. Particular attention was directed to the lateral interosseous ligaments of the distal phalanx and their possible function during gripping with the digital pulp.

Adipose Tissue↗
PubMed1975

Effects of antineoplastic agents on wound healing in mice.

The influence of antineoplastic agents on wound healing was evaluated in an experimental model employing surgical incisions in the skin of mice. A single injection in the therapeutic dose range of various clinically active antitumor agents was administered immediately following operation and the breaking strength of skin wounds was measured 3, 7, and 21 days later. Vincristine and methotrexate decreased wound strength at 3 days but not on days 7 or 21. Actinomycin D interfered with early phases of wound healing and had less effect on later phases. Treatment with bleomycin had no effect on wound strength at days 3 or 21 but prevented an increase in wound strength from day 3 to day 7; 1,3-bis(2-choroethyl)-1-nitrosurea (BCNU) decreased wound strength at all time points after operation, whereas 5-Fluorouracil had no significant effect at any time. The presence of a large tumor mass had no direct effect on wound strength nor did it modify the effect on wound strength of an antineoplastic agent, cyclophosphamide. These findings are discussed, taking into account the experimental and clinical literature on the effects of antitumor drugs on wound healing.

Animals↗
PubMed1974

Some inhibitory effects of (--)-emetine on growth of Ehrlich ascites carcinoma.

(-)-Emetine has little or no effect on O(2) consumption of Ehrlich ascites-cell suspensions or on the viability of transplanted Ehrlich ascites-tumour cells exposed to, or incubated with, the drug in vitro before inoculation into new-host mice. (-)-Emetine administered as a single injection to mice bearing Ehrlich ascites-tumour cells slows the growth rate of the tumour. The subcutaneous or intraperitoneal injection of the drug depresses protein and DNA synthesis of the tumour cells in vivo in a reversible manner. Mice bearing ascitic sarcoma 180 or Ehrlich ascites-tumour cells when given a course of treatment with (-)-emetine or (-)-O-methyltubulosine have a substantially lower tumour load than untreated controls and correspondingly longer survival times.

Animals↗