Antitumor effect of monoclonal antibody-carboplatin conjugates in nude mice bearing human ovarian cancer cells

Background. The antitumor effect and toxicity of immunoconjugates were studied in nude mice bearing a human ovarian cancer cell line, OVA-1. Methods. We studied the tissue distribution of an anti-cytokeratin-8 monoclonal antibody (6D7) in OVA-1-bearing nude mice by giving 6D7 labelled with ¹²⁵I. The immuno conjugate consisted of 6D7 and carboplatin (6D7-conjugate), coupled via carboxymethyl dextran, and this was intraperitoneally administered to OVA-1 bearing nude mice. The tumor volume and the body weight were measured for 5 weeks. Tissue platinum concentrations in the OVA-1 tumor, blood, liver, kidney, and spleen, were measured from 3 to 120 min after administration of the conjugate. The results were compared with those in nude mice treated with nonspecific mouse IgG coupled with carboplatin (IgG-conjugate) or carboplatin alone. Results. The coupling rate of the drug to 6D7 was approximately 80%, and was stable over several measurements at various times. In-vivo accumulation of 6D7 labelled with ¹²⁵I in the OVA-1 tumors was significantly higher than that in mice that received nonspecific mouse- IgG-¹²⁵I, with tumor/ blood radioactivity ratios of 14.0 and 1.28, respectively. The tumor growth rate in mice that were administered 6D7-conjugate was (at a maximum) 40% lower than the tumor growth rate in mice administered carboplatin. The body weight of the mice that received 6D7-conjugate did not decrease during the 5-week observation period, while the body weight of the mice that received carboplatin decreased by a maximum of 10%. In addition, upon administration of 6D7-conjugate, the platinum concentration in the tumor was maintained for a longer period than after the administration of carboplatin alone. Conclusions. The tumor growth suppression effect was significantly higher in the mice bearing the OVA-1 tumor that received 6D7-conjugate than in the animals that received carboplatin alone. This difference could be caused by differences in the platinum concentrations in the tumor between the two groups. Received: November 9, 1998 / Accepted: March 23, 1999     

C-kit Gene Abnormalities in Gastrointestinal Stromal Tumors (Tumors of Interstitial Cells of Cajal)

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the GI tract, and expresses KIT and CD34 in most cases. Gain-of-function mutation of the c-kit proto-oncogene has been described, but its significance in GIST has not yet been fully evaluated. Mutation in exon 11 of the c-kit gene was determined by both polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing in primary and metastatic GISTs and esophageal leiomyomas in Japanese subjects. C-kit gene mutation was identified in 15 of 48 primary GISTs (31%), four of seven metastatic GISTs, but none of the leiomyomas. Three mutations were mis-sense point mutations, and 16 were in-frame deletions of 3–48 bp. C-kit gene mutation was observed equally in low- and high-risk groups, and was not related to any clinical and pathologic factors, phenotypes or Ki-67 labeling index (LI) of tumor cells. In five of 15 deletion mutations (four in primary tumors and one in a metastatic tumor), the mutations were present at the distal location of exon 11 of the c-kit gene, which was a minor mutation in previous reports from Finland and the USA. C-kit gene mutations in GIST are not always related to a poor prognosis, but further comparative studies are necessary in Western and Japanese populations.     

Uptake and Intracellular Distribution of Amrubicin, a Novel 9-Amino-anthracycline, and Its Active Metabolite Amrubicinol in P388 Murine Leukemia Cells

Amrubicin, a 9-aminoanthracycline anti-cancer drug, and its C-13 hydroxyl metabolite amrubicinol, were examined for growth-inhibitory activity as well as cellular uptake and distribution in P388 murine leukemia cells and doxorubicin-resistant P388 cells. Also discussed are the differences in the mechanisms of action among amrubicin, amrubicinol and doxorubicin in terms of their cellular pharmacokinetic character. In P388 cells, amrubicinol was about 80 times as potent as amrubicin, and about 2 times more potent than doxorubicin in a 1-h drug exposure growth-inhibition test. A clear cross-resistance was observed to both amrubicin and amrubicinol in doxorubicin-resistant P388 cells, though the resistance index was lower for amrubicin. The intracellular concentration of amrubicinol was about 6 times and 2 times higher than those of amrubicin and doxorubicin, respectively. Compared to doxorubicin, amrubicin and amrubicinol were released rapidly after removal of the drugs from the medium. A clear correlation was found between the growth-inhibiting activity and the cellular level of amrubicin and amrubicinol in P388 cells. About 10 to 20% of amrubicin or amrubicinol taken up by the cells was detected in the cell nuclear fraction, whereas 70 to 80% of doxorubicin was localized in this fraction. These results suggest that amrubicin and amrubicinol exert cytotoxic activity via a different mechanism from that of doxorubicin.     

Abiraterone Followed by Enzalutamide Versus Enzalutamide Followed by Abiraterone in Chemotherapy-naive Patients With Metastatic Castration-resistant Prostate Cancer

Background

Abiraterone (AA) and enzalutamide (ENZA) are increasingly being used in chemotherapy-naive patients with metastatic castration-resistant prostate cancer owing to efficacy and favorable toxicity. However, the order in which they should be administered has not been determined.

Preventive effect of post-ischemic reperfusion injury by terminal Nicorandil-Mg cardioplegia]

In this study, we evaluated the postischemic myocardial tissue blood flow, specific enzymes, and functional recovery infused with a Nicorandil vasodilator-magnesium solution (Nico.: 8 mg/L, Mg: 20 mEq/L) given just prior to reperfusion (Terminal Cardioplegia, TCP). 27 patients undergoing valve replacement were divided into two groups; the hearts of group non-TCP (nTCP) (n = 15) were reperfused after ischemia without TCP, and in the other hearts of group TCP (n = 12), TCP was given for 2 min prior to reperfusion. During the reperfusion period, myocardial tissue blood flow (TBF) on the anterior wall of left ventricle were monitored by a laser blood flow-meter. Thereafter, serum CK-MB levels, MM3/MM1 values by CK-MM subbands (MM1, MM2, MM3) levels and LVSWI were measured until 24 hours after surgery. At 5 and 10 min of reperfusion, Group TCP had a significantly greater TBF than Group nTCP (5 min; G-TCP: 69.9 +/- 19.0 ml/100 g.min, G-nTCP: 47.5 +/- 20.9, p less than 0.05, 10 min; G-TCP: 74.9 +/- 22.8, G-nTCP: 56.1 +/- 23.4, p less than 0.05). At 3 hrs after surgery, an increase of MM3/MM1 values was significantly suppressed in Group TCP compared to Group nTCP (G-TCP: 2.6 +/- 0.6, G-nTCP: 3.4 +/- 1.0, p less than 0.05). Also, Group TCP had better recovery of LVSWI. These results indicate that the TCP might reduce the postischemic reperfusion injury by the improvement of myocardial TBF and metabolism.     

Stress management in large-scale establishments]

Due to a recent dramatic change in industrial structures in Japan, the role of large-scale enterprises is changing. Mass production used to be the major income sources of companies, but nowadays it has changed to high value-added products, including, software development. As a consequence of highly competitive inter-corporate development, there are various sources of job stress which induce health problems in employees, especially those concerned with development or management. To simply to obey the law or offer medical care are not enough to achieve management of these problems. Occupational health staff need to act according to the disease type and provide care with support from the Supervisor and Personnel Division. And for the training, development and consultation system, occupational health staff must work with the Personnel Division and Safety Division, and be approved by management supervisors.     

Age-specific relationship between blood pressure and the risk of total and cardiovascular mortality in Japanese men and women.

To examine the impact of age on the relationship between blood pressure (BP) levels and each of cardiovascular disease mortality and all-cause mortality, a total of 30,226 men and 58,798 women aged 40-79 years who had no history of stroke or heart disease underwent health checkups in Ibaraki-ken, Japan, in 1993 and were followed through 2002. Risk ratios for mortality by BP category based on the 1999 WHO-ISH guidelines were calculated by age subgroups (40-59 years, 60-79 years) using a Cox proportional hazards model. Compared with optimal BP levels, the multivariate risk ratios of cardiovascular mortality for stage 2 or 3 hypertension were 5.99 (95% confidence interval: 2.13-16.8) in middle-aged men and 4.09 (1.70-9.85) in middle-aged women. These excess cardiovascular mortality risks were larger in the 40-59 years age group than in the 60-79 years age group for both genders (p for interaction = 0.01 for both). In men, the population attributable risk percents of cardiovascular mortality were 60% for younger men and 28% for older men, while for women they were 15% for younger women and 7% for older women. Weaker but significant excess risks of total mortality were observed for stage 2 or 3 hypertension in men of both age groups and in the older age group for women. The impact of BP on the risk of cardiovascular mortality was larger among middle-aged persons than among the elderly in both men and women. Our findings indicate the importance of BP control to prevent cardiovascular disease among middle-aged individuals.     

Effect of myocardial preservation and preoperative left ventricular end-diastolic pressure upon the early postsurgical cardiac function after prosthetic cardiac valve replacement

We investigated the effect of myocardial preservation and preoperative stroke work index (SWI) and left ventricular end-diastolic pressure (LVEDP) upon the early postsurgical kinetics of left ventricular function in thirty-four patients after prosthetic cardiac valve replacement. They received both-sided cardiac catheterization and measurement of cardiac output by dye dilution method in a standard fashion. Myocardial temperature was measured simultaneously and consecutively during aortic cross-clamping period (greater than 70 min) on open heart surgery. Thereafter, each postsurgical left ventricular function was estimated at three, six, twenty-four and forty-eight hours after weaning from cadiopulmonary bypass (CPB) by using Swan-Ganz catheter. SWI0 X 1000/AnI was used as an improved index of postsurgical cardiac function, because it was incorporated with the preoperative left ventricular stroke work index (SWI0) and anoxic index (AnI), which was the integral of myocardial temperature during aortic cross-clamping period. Otherwise, we regarded LVEDP as an estimate of preoperative cardiac function. So we compared them with the early postsurgical left ventricular SWI, respectively. As a result, the relation between SWI0 and the postsurgical SWI (SWI24 and SWI48) showed positive correlations with correlation coefficients 0.52 and 0.70, and the relation between AnI and the early postsurgical SWI (SWI3 and SWI6) showed negative correlations with correlation coefficients -0.56 and -0.52. While the relation between SWI0 X 1000/AnI and postsurgical SWI (from SWI0 to SWI48) showed positive correlations with correlation coefficients decreasing from 0.76 to 0.57. LVEDP showed negative correlations to SWI0 and SWI48 with correlation coefficients -0.48 and -0.45.(ABSTRACT TRUNCATED AT 250 WORDS)