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Biomedical subjects

M Inaba

Publications and source records attributed to M Inaba.

At least 451 records · Page 25Linked to original sources
PubMed1982

Reduction of lethal toxicity of chloroethylnitrosoureas by sugar alcohols without loss of antitumor activity.

Sugar alcohols, such as mannitol, sorbitol, galactitol, and inositol, selectively reduced the acute lethal toxicity of 1-(2-chloroethyl)-3-(methyl alpha-D-glucopyranos-6-yl)-1-nitrosourea (MCNU) without reducing its antitumor activity. Fifty mg MCNU/kg killed all CD2F1 mice within about 10 days, while the administration of 3,000 mg sugar alcohols/kg immediately prior to MCNU protected mice from the lethal toxicity and all survived. The amelioration of MCNU toxicity by sugar alcohols was dose-dependent. Pretreatment with mannitol 1 day before MCNU administration was effective. In addition, a series of five daily treatments with lower doses of mannitol was also effective. This protection was accompanied by the reduction of both body weight loss and myelosuppression. The antitumor effects of MCNU on P388 leukemia and Lewis lung carcinoma were not significantly altered by mannitol treatment. These phenomena were not limited to MCNU, the lethal toxicity of GANU, ACNU, Me-CCNU, and mitomycin C also being reduced by mannitol treatment.

Animals↗
PubMed1982

Characteristic distribution of two forms of chromatin-bound RNA polymerase II in rat liver nuclei.

We have shown that, in rat liver nuclei, the chromatin-bound RNA polymerase II is released as two different forms on digestion with micrococcal nuclease or DNase I (peak 1 and peak 2). To elucidate the origin of the two forms of the enzyme, we examined their distribution in fractionated chromatins obtained by mild micrococcal nuclease digestion of the nuclei. About half of the total peak 2 activity was recovered in a nuclease-sensitive chromatin fraction which contained DNA enriched in the sequences appearing in the polysomal polyadenylated mRNA. On the other hand, four-fifths of the total peak 1 activity was recovered in a nuclease-resistant chromatin fraction which contained DNA comprising only two thirds of the transcribed sequences. Furthermore, during the nuclease digestion, peak 2 activity was rapidly released from the chromatin, whereas peak 1 activity was gradually released. These results indicate that the two forms of RNA polymerase II are distributed differently in the cell nuclei.

Animals↗
PubMed1982

A case report on disequilibrium hypercalcemia in hyperthyroidism. Comparison of calcium metabolism with other patients with hyperthyroidism.

The patient, a 30-year-old woman, was admitted to Itoh Hospital in February, 1979 for hyperthyroidism. She had a history of pyelonephritis and recurrent urinary tract infection. Laboratory data on admission revealed overt hyperthyroidism (T3: 405 ng/dl, T4: 22.5 micrograms/dl and T3U: 57.--%), severe hypercalcemia of 12.6 mg/dl and hypercalciuria. The PSP excretion and GFR were both decreased. Serum c-PTH was nondetectable. As the thyroid function improved, there was a gradual decrease and later normalization of plasma calcium, phosphate and urinary calcium excretion. When subtotal thyroidectomy was performed on October 19, 1979, hypertrophy of the parathyroid gland was not demonstrated. In comparison with 98 other hyperthyroid patients, the pathogenesis of hypercalcemia was discussed. In conclusion, hypercalcemia in the patient, T. Y., was regarded as a kind of disequilibrium hypercalcemia which resulted from a combination of increased bone turnover and decreased calcium excretion by the kidney.

Adult↗
PubMed1982

New antitumor imidazole derivative, 5-carbamoyl-1H-imidazol-4-yl piperonylate, as an inhibitor of purine synthesis and its activation by adenine phosphoribosyltransferase.

The mechanism of action of 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250), which has a broad antitumor spectrum, was examined by in vitro cell culture and enzymatic studies. In the serum-containing culture medium, SL-1250 was rapidly deacylated to 4-carbamoylimidazolium 5-olate (SM-108). Thus, SL-1250 might be acting on the cells in the form of SM-108. The growth of L5178Y cells was completely inhibited by 10(-5) M SL-1250. It should be noted that this growth inhibition was significantly reversed in the presence of equimolar concentrations of guanine, guanosine, or guanosine 5'-monophosphate to those of SL-1250. However, hypoxanthine and xanthine were not effective. These effects of purine addition were observed to be quite similar in growth inhibition by SM-108. It was found that inosine 5'-monophosphate dehydrogenase (EC 1.2.1.14; IMP dehydrogenase), a key enzyme of de novo purine synthesis, from Ehrlich carcinoma cells was inhibited by SM-108 only when 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) and MgCl2 coexisted with SM-108. In contrast, a chemically synthetic ribonucleotide of SM-108 inhibited IMP dehydrogenase without PRPP and MgCl2, and the mode of inhibition was competitive with the Ki value of 2 x 10(-8) M. On the other hand, the inhibition of either growth of L5178Y cells or IMP dehydrogenase in the presence of PRPP and MgCl2 by these compounds was reversed by adenine. A nucleotide of SM-108 was chromatographically identified when [14C]SM-108 was incubated in the enzyme solution with PRPP and MgCl2. This conversion by enzyme was also inhibited by adenine. Viewed together, these results strongly suggest that SL-1250 is, after being converted to SM-108, activated to its nucleotide form by adenine phosphoribosyltransferase (EC 2.4.2.7) and that this SM-108 nucleotide blocks de novo synthesis of guanosine 5'-monophosphate by inhibiting IMP dehydrogenase.

Adenine Phosphoribosyltransferase↗
PubMed1982

Collateral sensitivity of 6-mercaptopurine-resistant sublines of P388 and L1210 leukemia to the new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate and 4-carbamoylimidazolium 5-olate.

Two new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250) and 4-carbamoylimidazolium 5-olate (SM-108), were investigated for their antitumor activities against 6-mercaptopurine (6-MP)-resistant sublines of P388 and L1210 leukemia. It was found that both resistant sublines exhibited collateral sensitivity instead of cross-resistance to these new antipurine drugs. Since more potent cytotoxic activities of these drugs against 6-MP-resistant cells were observed even in vivo cell culture systems, this collateral sensitivity was proved on a cellular basis. Biochemical studies revealed that 6-MP-resistant sublines of both P388 and L1210 leukemia are deficient in hypoxanthine-guanine phosphoribosyltransferase activity. In these cells, not only the activation of 6-MP to its nucleotide but also the synthesis of guanosine 5'-monophosphate via the salvage pathway seems to be severely restricted. However, SL-1250 and SM-108 can be activated to their nucleotide even in these 6-MP-resistant cells because the activation of these compounds is proceeded by adenine phosphoribosyltransferase. In conclusion, suppression of de novo purine synthesis with SL-1250 and SM-108 seems to be a very efficient means of killing these 6-MP-resistant cells, which lack a salvage pathway for guanosine 5'-monophosphate.

Animals↗
PubMed1982

[General observation on drug resistance of cancer cells].

General discussions on the drug resistance of cancer cells were made from various points of view: (1) drug resistance as an unhereditary phenotype, (2) changes in the cell population during drug treatment, (3) acquired resistance and natural resistance, (4) general concepts on biochemical and pharmacological mechanisms for drug resistance, (5) common mechanism for concurrent resistance to DNA-intercalators and vinca-alkaloids, and (6) collateral sensitivity on a cellular basis.

Animals↗
PubMed1982

Occurrence of drug resistance in human tumor implanted in nude mice.

A line of human breast tumor xenograft in nude mouse, MX-1, acquired resistance to vincristine or mitomycin C during multiple treatments; both drugs were effective against the parent line of this tumor. If the treatment was started when the tumor was smaller than 500 mm3 in size, MX-1 was responsive to the initial treatment with vincristine (0.8 mg/kg) or mitomycin C (3.4 mg/kg), and some animals survived with complete regression of the tumor. However, some of the recurrent tumors were able to tolerate multiple treatments with either of these agents, and finally acquired apparent resistance to the agent. On the other hand, when tumors larger than 5,000 mm3 were treated with vincristine, the occurrence of resistance was observed with much higher frequency than when small tumors were treated. Resistant tumors thus obtained exhibited significant refractoriness to each agent when they were reimplanted in new mice and treated in the same manner. This suggests that the occurrence of resistance can be ascribed to changes not in metabolic functions of the host animal but in the tumor cell populations.

Animals↗
PubMed1982

Biochemical characteristics of a 5-fluorouracil-resistant subline of P388 leukemia.

A 5-fluorouracil (5-FU)-resistant cell line of P388 mouse leukemia was established by intraperitoneal treatment with the drug. The activities of enzymes responsible for the formation of 5-fluoro-2'-deoxyuridine 5'-monophosphate and 5-fluorouridine 5'-monophosphate from 5-FU, the quantities of 5-FU metabolites, and the permeability to 5-FU were determined in both the 5-FU-sensitive and the resistant cell lines. It was found that the activities of uridine kinase and uracil phosphoribosyltransferase, the initial uptake of 5-FU, and the intracellular levels of 5-FU-nucleotides were all decreased in the resistant cells. However, the initial uptake of 5-FU into cells preincubated with KCN was the same in the sensitive and the resistant cells. These results support the view that the ineffectiveness of 5-FU against the resistant cell line of P388 leukemia can be attributed to decreases in the activities of enzymes responsible for the formation of 5-FU-nucleotides and probably also decreased transport of 5-FU in the resistant cells.

Animals↗
PubMed1981

Regeneration of axillary hairs after plucking.

Studies on the regeneration of axillary hairs after plucking are described. Regeneration of axillary hairs after plucking was recognized as originating in a special region of the upper isthmus of the hair apparatus, from which point solid pegs of epithelial cells grow downward and form inner root sheaths. New hairs form in their centers. At this stage, the lower parts of the hair follicles descend while the new hairs grow from the centers of the pegs by vigorous mitosis of germinal cells. Eventually, the epithelial cells wrap around masses of mesenchymal cells and form new bulbs from which hair shafts grow upward. The new matrices acquire new complements of functioning melanocytes.

Axilla↗
PubMed1981

Clinical observations on the development and eventual character of hair in the axillae of human beings.

The authors examined clinically growth and patterns of axillary hair of Japanese males and females of various ages with a specific interest in the differences between vellus and coarse hairs. One notable finding was that in the axillae of children, vellus hairs are equidistant and solitary, whereas the coarse hairs that replace them emerge during puberty as solitary hairs and in bundles or groups. A statistical summary and speculation as to why growth of vellus hair and growth of coarse hair differ are the substance of this report.

Adolescent↗
PubMed1981

Effects of adrenal demedullation and peripheral noradrenaline-depleting agents on adrenocortical function and spleen in rats.

Adrenocortical functions of adrenal-demedullated rats (ADMx rats) and peripherally chemical-sympathectomized ADMx rats were studied by examining changes in the levels of serum and adrenal corticosteroids (CS). Resting levels of serum and adrenal CS were not influenced by adrenal-demedullation and peripheral chemical-sympathectomy with 6-hydroxydopamine. Diurnal variation in serum CS concentration was also unchanged, suggesting that peripheral adrenergic systems do not influence the basal function of hypothalamo-pituitary-adrenocortical axis. Exposure of ADMx rats to the stressful stimuli, however, resulted in lowered adrenocortical response with a lesser increase in serum CS concentration, while peripheral chemical-sympathectomy of ADMx rats with 6-hydroxydopamine or guanethidine caused a significant enhancement of adrenocortical response to the stress with elevation of the serum CS concentrations. These findings suggest that increased peripheral adrenergic activity may suppress the activation of the hypothalamo-pituitary-adrenocortical system as the animals were exposed to the stressful stimuli. Adrenal-demedullation produced no increase in spleen weight while chemical-sympathectomy by peripheral administration of 6-hydroxydopamine did produce a significant increase in the weight of this organ. Histological features following chemical-sympathectomy are described.

Adrenal Cortex↗
PubMed1981

Antitumor activity of 7-n-(p-hydroxyphenyl)-mitomycin C in experimental tumor systems.

The antitumor activity of 7-N-(p-hydroxyphenyl)-mitomycin C (M-83) was compared with that of mitomycin C (MMC) in rodent tumor systems. M-83 exhibited more potent activity than MMC against the ascitic form of lymphocytic leukemia P388 and fibrosarcoma Meth 1, and doses of over 5 mg/kg of M-83 (1/6 LD50) resulted in some 60-day survivors. The chemotherapeutic ratio (optimal dose/MED) of M-83 was around 64 and was estimated to be approximately 5 to 8 times higher than that of MMC. Upon intravenous administration, M-83 also gave a better survival and showed a higher chemotherapeutic ratio than MMC against intravenously implanted P388. M-83 inhibited the growth of solid form of sarcoma 180 to the same extent as MMC at an equivalent dose, but showed a higher safety margin than MMC. M-83 was as effective as MMC against Lewis lung carcinoma at dose levels giving the same degree of toxicity. In vitro studies on tumor growth inhibition demonstrated that the cytotoxic effects of M-83 against leukemia P388 and fibrosarcoma Meth 1 cells were similar to and stronger than those of MMC, respectively.

Animals↗
PubMed1981

Comparison of the hematologic toxicity of 7-N-(p-hydroxyphenyl),-mitomycin C and mitomycin C.

7-N-(p-Hydroxyphenyl)-mitomycin C (M-83), a new analog of mitomycin C (MMC) with equivalent or greater antitumor potencies against various experimental tumors, was investigated to determine its hematologic toxicity in mice. M-83 showed a significantly lower toxicity than MMC with respect to myelosuppression and leukopenia when compared at equivalent effective doses. In M-83-treated mice, the damage to the bone marrow was much milder at the nadir point and the recovery from myelosuppression to the normal level was faster as compared with that in the case of MMC. As a result, the number of white blood cells in the peripheral blood of the M-83-treated groups was considerably greater than that in the MMC-treated ones. These findings suggest that M-83 may be effective in clinical use.

Animals↗