Biomedical subjects
Publications and source records attributed to Y Kimoto.
The cytotoxicity of human peripheral blood lymphocytes against malignant tumor cell lines was significantly inhibited by human plasma or sera. In addition to so-called blocking factors such as antigens, antibodies, antigen-antibody complexes, IAP and ferritin, some substances which could be removed by heat or centrifugation were considered to play a significant role.
Mouse monoclonal antibody 17-1A-dependent cellular cytotoxicity hardly revealed any killer activity in the presence of human plasma, nor did 17-1A show complement-dependent cytotoxicity. ADCC of 17-1A-armed effector cells was also inhibited by human plasma. These results were caused by the inhibition of 17-1A binding to the Fc receptors of effector cells.
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The combined effect of human interferons and chemotherapeutic agents on human gastric cancer cell lines and a human pancreatic cancer cell line was studied in vitro. Interferons, when used as a single drug, showed inhibitory effects in the order, gamma greater than beta greater than alpha. However, there was no significant difference between the effects of natural and recombinant interferon. In combination therapy, the chemotherapeutic agents should be administered first, followed by administration of interferon(s), since this method showed the most inhibitory effect. Low concentration of 5-FU (0.001-0.01 microgram/ml) or methotrexate (0.01-1 microgram/ml) was able to inhibit the growth of cell lines when combined with interferon. These results suggested that in clinical use, low amounts of chemotherapeutic agents followed by administration of interferon(s) could be available with minimum side effects and with more pronounced anticancer effects.
The antiproliferative effect of human recombinant interferon alpha, beta and gamma was studied in vitro in combination. Growth of human gastric cancer cell lines and a pancreatic cancer cell line was inhibited markedly by combination of interferons beta and gamma or a combination of all three interferon types. Combination of low-dose interferons (50-100 units/ml) was more effective than a high dose of single interferon. Moreover, human pancreatic cancer cells were completely eliminated after incubation with 5-fluorouracil (0.001 microgram/ml) or methotrexate (0.1 microgram/ml) combined with interferons beta and gamma (50 units/ml each). These results suggested that combination of interferons beta and gamma could be the most effective interferon therapy for cancer.
The cytocidal effect of human peripheral blood lymphocytes (PBL's) enhanced by human recombinant interleukin 2 (IL-2) on human colon carcinoma cell line SW1116 was examined in vitro in the presence of plasma from patients with recurrence of colorectal carcinoma. In addition, human recombinant interferons alpha, beta, and gamma were combined to enhance this cytotoxicity of PBL's. Cytotoxicity of PBL's was enhanced by IL-2. Patients' plasma blocked the cytotoxicity of PBL's. Serially added IL-2 was able to maintain the enhanced cytotoxicity of PBL's in the presence of patients' plasma. The mixture of interferons (alpha + beta + gamma, or beta + gamma) directly killed target cells more efficiently than with single use of each interferon or other combinations of interferons. These mixtures of interferons (alpha + beta + gamma, or beta + gamma) also activated cytotoxicity of PBL's. The cytotoxicity of IL-2-activated PBL's was further enhanced by intermittent addition of the interferon mixture.
The effectiveness of LAK cells (lymphokine-activated killer cells) on malignant tumors in vivo and in vitro was discussed. LAK cells induced from lymphocytes by interleukin-2 (IL-2) were able to kill target malignant cells in a nonspecific manner. Combination of IL-2 enhanced LAK activity. Adoptive immunotherapy with LAK cells and IL-2 carried out in the USA has produced effective results in several cases; complete regression of skin metastases of malignant melanoma and partial regression of other malignancies. However, high doses of IL-2 mediated a toxic side effect, capillary permeability leak syndrome. Our studies have revealed that LAK cells after one to two weeks incubation do not require such a high concentration of IL-2, and that adoptive immunotherapy using such, LAK cells and IL-2 can be carried out safely.
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The effects of electrical and chemical stimulation on the mechanical or electrical properties of the circular smooth muscle cells of the bladder neck, and proximal urethra of the male rabbit were investigated by means of micro-electrode, double-sucrose-gap and tension-recording methods. In the bladder neck, application of short current pulses (50 microseconds) produced an initial excitatory junction potential (e.j.p.) with a superimposed spike, followed by a late depolarization, and these electrical events evoked contraction. The initial e.j.p. was unaffected by guanethidine, phentolamine, methysergide or mepyramine, indicating the initial e.j.p. is not mediated by activation of adrenergic, tryptaminergic or histaminergic receptors. The late depolarization was enhanced by pre-treatment with neostigmine (10(-7) M) and abolished by atropine (10(-6) M). In the proximal urethra, electrical-field stimulation evoked phasic contraction which was followed by relaxation, associated with initial e.j.p.s, late depolarization and inhibitory junction potentials (i.j.p.s). Guanethidine (10(-5) M) or phentolamine (10(-6) M) reduced the size of the initial e.j.p. to 40-50% of the control value and combined application of guanethidine and atropine further reduced the amplitude of the e.j.p. to 20-30%. There was a parallel reduction in the mechanical response. The late depolarization was enhanced by neostigmine and abolished by atropine. The i.j.p. and muscle relaxation were not affected by propranolol, phentolamine, guanethidine or atropine. These results indicate that the proximal urethral smooth muscle cells are innervated by adrenergic and cholinergic excitatory, and by non-cholinergic non-adrenergic inhibitory nerve fibres. In the prostatic urethra, field stimulations also evoked twitch contractions with or without following phasic contraction and relaxation. The twitch contractions were abolished by d-tubocurarine (10(-6) M), suggesting that they arise from striated muscle. Exogenously applied prostaglandin (PG) E1, PGE2 or PGF2 alpha (greater than 10(-10) M) evoked sustained increase in the muscle tone in the presence or absence of indomethacin, and enhanced the amplitude of muscle relaxation evoked by the field stimulation without affecting the resting membrane potential. Indomethacin (10(-6)-10(-5) M) gradually reduced the muscle tone of the proximal urethra with no change in the resting membrane potential. At the reduced muscle tone, electrical-field stimulation did not evoke muscle relaxation. Thus, the amplitude of muscle relaxation evoked by field stimulation was dependent on the level of muscle tone of the circular muscle strips.(ABSTRACT TRUNCATED AT 400 WORDS)
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Experimental chemotherapies for 15 human cancers xenografted into nude mice were performed using 14 anticancer agents including 6 drugs in clinical use. Treatment with each single agent was performed for every cancer line using the maximum tolerated dose through continuous daily (antimetabolites) or intermittent (cytocidal agents) schedules. Effectiveness of each drug was evaluated by inhibition rate (IR) calculated from mean tumor weights of both treated and untreated groups. Response to a treatment was judged as effective when the IR was higher than 58%. Response rate of each drug was as follows; MMC was 67%, UFT 67%, CPA 47%, FT-207 40%, ACNU 33%, ADR 27%, SOAz 87%, 5'-DFUR 80%, MXT 20%, Leakadine 17%, M-83 17%, CAM 0% and GANU 0%. Generally, the experimental results for each drug on the xenografts was in good accordance with the known clinical effect of each drug on the same type of cancer. On the other hand, individual cancer xenografts showed considerable differences in chemosensitivity. Some tumors were sensitive to a majority of the drugs, whereas some were resistant to many of them. Each cancer line seemed to retain individuality in its spectrum of chemosensitivity irrespective of whether it originated from the same organ or whether it was of similar histologic type. This fact suggests the necessity of selecting drugs effective to the individual tumor when considering a patients chemotherapy regime.
As a tumor factor possibly responsible for chemosensitivity of human cancer xenografts in nude mice, the vascular architecture of tumors growing in mice was investigated in 15 kinds of cancer lines. These consisted of 7 gastric, 3 colorectal, 3 breast and 2 pancreatic cancers. Whole body angiograms of tumor-bearing mice were obtained by perfusing a radiopaque silicone rubber compound (Microfil) through the left ventricle of each mouse. Each cancer retained a characteristic vascular architecture comparable to its histopathological finding. According to the vascularity of the viable part of the tumor, the 15 lines of cancer were classified into 5 groups. Compared with colorectal cancers, stomach cancers had a tendency to decline to a more hypervascular group. There was no apparent relation between vascularity and growth rate, or histological differentiation of the tumors. Among 14 anticancer agents studied, statistically significant correlation between chemosensitivity and vascularity of the 15 cancer lines was observed in 2 drugs, 5'-DFUR and adriamycin. The vascular architecture of the tumors would have some influence in their chemosensitivity through drug accessibility to cancer cells.
A newly developed human immunoglobulin for intravenous use, SM-4300, purified by cold ethanol precipitation and ion exchange resin, has been studied in the surgery. SM-4300 has been evaluated clinically against inpatients with severe bacterial and/or fungal infections in the combined use with the antibiotics which were resistant to antibiotic therapy. Total number of 13 patients affected with various severe infections were treated with SM-4300. Clinical effects of SM-4300 were excellent in 2 cases, good in 6, fair in 3 and poor in 2. The efficacy rate was summarized as 61.5%. No subjective and objective clinical side effects and abnormal laboratory findings were observed. In conclusion, combination therapy with SM-4300 and antibiotics was considered to be safe and effective against severe bacterial and/or fungal infections in the surgery.
Mass screening for breast cancer has been carried out in 13 cities in Osaka Prefecture for the past 15 years. The screening method was inspection and palpation by the physician, and examination by mammography was performed for the women with abnormal findings as the second screening. Among the total of 73,488 examinees (actual number was 44,835 examinees) 3,022 (4.1%) were examined by mammography and 106 (0.14%) patients with breast cancer were detected. Seventy-two of them were found at the first screening, 15 at the subsequent screening, and 19 were interval cases. Sixty-two cases of breast cancer (63.9%) were without lymph node metastasis, and cancer in Stage I and TIS reached 37.8% in this series. These results show that our screening method is valid for detecting the earlier stages of breast cancer.
The effects of trimebutine maleate (TM-906) on electrical and mechanical activities of smooth muscles of the guinea-pig stomach were investigated using a microelectrode and isometric tension recording methods. TM-906 (2 X 10(-5) M) depolarized the membrane of smooth muscles in the antrum to about 10 mV. From the current-voltage relationship and changes in membrane potentials in various [K]0, the TM-906-induced depolarization is considered to be mainly due to a decrease in the K-conductance. TM-906 increased the amplitude of the first spike potential and regularized the rhythm of slow waves. These excitatory effects are presumably due to the K-channel-blocking action during the repolarizing phase of the spikes and to the depolarization. TM-906 reduced the amplitudes of mechanical activities and slow waves. These inhibitory effects are presumably due to the inhibition of Ca-release from storage sites and to the block of Ca-influx. The biphasic effects are possibly due to the local anesthetic properties. TM-906 modified neither the membrane potential nor the membrane conductance of circular muscles in the fundus. This may mean that the circular muscles in the fundus lack the K-channel sensitive to TM-906.
We conducted a mass screening survey for colorectal cancer by the combination of fecal occult blood tests under a restricted diet and a medical questionnaire in 7,392 healthy volunteers. Further diagnostic work-up was needed in 1,934 (26.2%) individuals. Of these, 1,409 (72.9%) showed occult blood in at least one slide, 245 (12.7%) had symptoms and 306 (15.8%) had a positive family history. Proctosigmoidoscopy, barium enema and flexible colonoscopy were performed in 1,251, 779 and 95 persons, respectively. Colorectal cancers were detected in 10 individuals (0.14%); 5 of these were in the early stage.
Fine structure of poorly differentiated adenocarcinoma selectively induced in the canine stomach by a low concentration of N-ethyl-N'-nitro-N-nitrosoguanidine was studied with special reference to the so-called signet ring cells. These cells were electron microscopically classified into two groups: 1) mucin-containing cells and 2) intracellular microcyst cells. The cytoplasm of mucin-containing cells was packed with fused large and low electrondense secretory granules. In another type of signet ring cells, there were intracellular microcysts with microvilli on the internal surface. A comparison of canine and human signet ring cells revealed a close resemblance in the fine structure. Canine gastric carcinoma should be a good model for human gastric carcinoma therapeutics.
Effect of intraarterial infusion chemotherapy on metastatic liver tumor (28 cases) of colo-rectal cancer was compared with that of oral or intravenous chemotherapy (8 cases). The efficacy of the selective intraarterial chemotherapy was 40%, non-selective intraarterial chemotherapy, 11.1% and oral or intravenous chemotherapy 0%, respectively. Mean survival time of the intraarterial chemotherapy was 11.1 months, and that of oral or intravenous chemotherapy was 6.0 months, suggesting greater efficacy of the intraarterial infusion chemotherapy. Especially, the selective intraarterial infusion chemotherapy will be an effective therapy for inoperable metastatic liver tumor.