Antitumor activity of 7-N-[[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]]-mitomycin C

Through the extensive investigation of new mitomycin C (MMC) derivatives, several compounds with disulfide at N-7 were found to show activities superior to MMC against murine Sarcoma 180 solid tumor. Among them, 7-N-[[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]]- mitomycin C (KW-2149) was selected for further evaluation of antitumor activity and toxicity in mice. KW-2149 exhibited activity superior to MMC in increasing survival of i.p. inoculated P388 leukemia-, M5076 sarcoma-, and B16 melanoma-bearing mice. KW-2149 administered i.v. also exhibited superior activity in inhibiting the growth of s.c. inoculated P388 leukemia, M5076 sarcoma, and colon 26 adenocarcinoma and in increasing survival of i.v. inoculated P388 leukemia- and M5076 sarcoma-bearing mice. Furthermore, KW-2149 remarkably increased the life span of MMC-resistant P388 leukemia- and L1210 leukemia-bearing mice. KW-2149 and MMC inhibited the growth of human tumors inoculated into nude mice. The activity of KW-2149 was prominent in human lung carcinoma Lu-65 and Lu-99, bladder carcinoma T24, and epidermoid carcinoma A431. KW-2149 was comparable to MMC in decreasing the number of WBC in the peripheral blood, and the thrombopenia induced by KW-2149 was mild and recovery was rapid. The in vitro anticellular spectrum of KW-2149 against 23 human tumor cell lines was similar to that of MMC. However, KW-2149 inhibited the growth of the cell lines at concentrations of 10- to 100-fold lower than MMC and showed efficient cytotoxicity against MMC-insensitive tumor cell lines. These included lung epidermoid carcinoma Calu-1, stomach carcinoma MKN-28, colon adenocarcinoma DLD-1, colon adenocarcinoma LoVo, bladder carcinoma HT-1197, sarcoma G-292, and melanoma SK-MEL-28 cells. These results indicate that KW-2149 bears interesting characteristics as a new anticancer drug and warrants further development.     

Adrenocortical carcinoma: report of a case]

A 24-year-old man visited our hospital complaining of hypertension and headache. Endocrinological findings revealed no abnormalities except for a slight decrease in serum adrenocorticotropic hormone (ACTH), a slight increase in urine 17-ketosteroid (17-KS), and a marked increase in serum pregnenolone. Computed tomography and magnetic resonance imaging revealed a 3 x 3 cm mass in the right adrenal area and I131-aldosterol scintigraphy demonstrated a high absorption of the isotope in the right adrenal area. Vena cavography suggested a 2 x 2 cm tumor thrombus originating in the right adrenal. Under the diagnosis of the right adrenocortical carcinoma, adrenalectomy and removal of the tumor thrombus were performed. Both serum pregnenolone and urine 17-KS returned to the normal level within a week after the operation and blood pressure was well controlled without any medication 3 months after the operation. Thus, the tumor seemed to be endocrinologically active.     

Severe Atopic Manifestations after Varicella in a Young Iffant

A 3 1/2-month-old girl developed aggravating atopic dermatitis and asthmatic bronchitis in the convalescence of her severe varicella, infected simultaneously with her mother following her brother. She had a marked eosinophilia and an elevated level of IgE. Clinical symptoms improved in parallel to the improvement of labolatory values within fortnight.     

Increase in cerebrospinal fluid and plasma levels of 3-methoxy-4-hydroxyphenylglycol in acute stroke

BACKGROUND AND PURPOSE: 3-Methoxy-4-hydroxyphenylglycol is known to be a principal metabolite of brain norepinephrine and to be released into the blood and cerebrospinal fluid in association with activation of the central noradrenergic system. We examined changes in plasma and cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol during acute stroke to see if there might be a correlation between these and the patient's clinical state. METHODS: We measured plasma levels of 3-methoxy-4-hydroxyphenylglycol in 32 control subjects and in 50 patients with brain hemorrhage and 57 patients with brain infarction who were admitted to the hospital within 72 hours after onset. In addition, we estimated 3-methoxy-4-hydroxyphenylglycol concentrations in the cerebrospinal fluid of 37 patients with brain infarction and eight control patients. RESULTS: Mean +/- SEM values for plasma 3-methoxy-4-hydroxyphenylglycol in the patients with brain hemorrhage and those with brain infarction were 7.3 +/- 0.5 and 6.6 +/- 0.5 ng/ml, respectively. Both values were significantly higher than that obtained in the 32 control subjects (4.6 +/- 0.3 ng/ml, p less than 0.01). Plasma levels of 3-methoxy-4-hydroxyphenylglycol correlated well with state of consciousness and prognosis. The mean +/- SEM level of 3-methoxy-4-hydroxyphenylglycol in the cerebrospinal fluid of the 37 patients with brain infarction (10.9 +/- 0.6 ng/ml) was also significantly higher than that in the eight control patients (7.9 +/- 0.6 ng/ml, p less than 0.01). CONCLUSIONS: The observed increase in plasma and cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol implies that the activity of the central noradrenergic neurons may be enhanced at the onset of stroke, and these levels may be related to some extent to the clinical state and prognosis of stroke patients.     

Alteration ratio of lung field CT numbers of full inspiration to end expiration scans in chronic obstructive pulmonary diseases]

The alteration ratio of lung field CT numbers in different respiratory phases was studied in 52 patients with chronic pulmonary obstructive disease (COPD) and 20 subjects with normal lung. The 52 patients with COPD consisted of 30 with clinically diagnosed chronic pulmonary emphysema (CPE), 15 with suspected CPE (sCPE) and seven with bronchial asthma (BA). The 20 subjects with normal lung were divided into two groups according to age. CT images were obtained in each case under different respiratory conditions, i.e., full inspiration and end expiration. The following parameters were employed for numerical evaluation: %(I-E)Apex = (MLDApexI-MLDApexE/MLDApexE x 100 %(I-E)Mid = (MLDMidI-MLDMidE)/MLDMidE x 100 %(I-E)Base = (MLDBaseI-MLDBaseE)/MLDBaseE x 100 %(I-E)Whole = (MLDWholeI-MLDWholeE)/MLDWholeE x 100 where MLD is mean lung density and the letters I and E stand for full inspiration and end expiration, respectively. The small letters Apex, Mid, Base and Whole stand for apex cut, mid-thorax cut, base cut and whole lung, respectively. The values of %(I-E)Whole were significantly different between disease groups except for those between the sCPE and BA groups. The values of %(I-E)Whole showed a good positive correlation with FEV1.0% (r = 0.79) and V25/H (r = 0.80) and a good negative correlation RV/TLC (r = -0.75). Diagnostic differentiation of COPDs by %(I-E)Whole values identified 80% of CPE cases and 91% of normal lung cases. In the sCPE group, the values of %DLco in patients with %(I-E)Whole above 9% were smaller than those in patients with %(I-E)Whole under 9%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of potassium on adrenergic nerve endings in bovine mesenteric lymphatics

This work concerned the effect of KCl (60 mM) on noradrenaline efflux from aminergic nerve endings in bovine mesenteric lymphatics. In high potassium Krebs solution containing cocaine (10(-7) M), the lymphatics showed some phasic contractions followed by a tonic contraction with a high initial peak. The high KCl solution also caused a transient but statistically significant increase of tritiated noradrenaline efflux (P less than 0.01) which was not blocked by tetrodotoxin (10(-7) M). However, 5 X 10(-6) M 5-hydroxytryptamine or 10(-5) M prostaglandin F2 alpha produced a contraction of the lymphatic smooth muscle similar in magnitude to the contraction by 60 mM KCl. In this case, however, no increase was observed in 3H efflux. A Ca-antagonist, D-600 (10(-4) M) inhibited the potassium-induced rise in tritiated noradrenaline efflux and suppressed dose-dependently the contractile response to high potassium solution. These observations support the suggestion that the effect of KCl on 3H-release reflects an effect of kinetics of exchange across the nerve ending rather than an effect of contraction per se on isotope exchange through the complex extracellular matrix, and that the activation of Ca channels in the adrenergic nerve terminals may contribute to the release of noradrenaline in high KCl solution.