Antitumor agents including mitomycin C (MMC) and methotrexate (MTX) were coupled to monoclonal antibodies against murine bladder tumor cell line MBT-2 for the purpose of enhancing their drug activity. MMC was conjugated with antibody through two carriers, periodate-oxidized dextran and dithiopyridylated serum albumin, and MTX was conjugated with antibody either directly or through dithiopyridylated serum albumin or poly-L-lysine via an amide bond. These conjugates were assayed for growth inhibitory effect on MBT-2 bladder tumor cells, MCA clone 15 embryo cells and P388 leukemic cells. The cytotoxicity tests demonstrated that drug-antibody immune conjugates were 10 to 100 times more cytotoxic against antibody-reactive MBT-2 cells than nonimmune drug conjugates and showed a similar level of cytotoxicity against antibodynonreactive cells to that of the nonimmune conjugates. This selective cytotoxicity was also confirmed by competitive inhibition of unconjugated antibody, showing a dependency on antibody binding to the target cell surface antigens. The targeting effect was further assessed by evaluating the suppression of tumor growth subsequent to in vitro treatment of MBT-2 cells with immune conjugates. Half of the mice receiving cells treated with immune conjugates survived more than 40 d after inoculation, while none or one of 7 mice receiving cells treated with unconjugated drug, antibody alone or nonimmune conjugates survived at 40 d after inoculation.Keywords--mitomycin C; methotrexate; drug-monoclonal antibody conjugate; selective cytotoxicity; murine bladder tumor cell; cell surface antigen The idea of targeting cytotoxic agents was proposed by Ehrlich at the beginning of the century,1) but such a goal has become feasible only with the recent advent of monoclonal antibody production.2) Monoclonal antibodies, because of their purity and specificity, and the ability to obtain them in large quantities, represent very attractive carriers for tumor therapeutic agents.3) Many cytotoxic agents coupled with monoclonal antibodies have been proposed and investigated for cancer chemotherapy with various degrees of success.4) Among them, immunotoxins prepared by coupling biological toxins to antibodies have received much attention because of their enormous cytotoxic potential.5) Such an approach would, however, appear to require absolute tumor specificity of monoclonal antibodies in order not to damage normal tissues, and it is probably unrealistic to expect to obtain such truly tumor-specific antibodies. An alternative is to couple conventional chemotherapeutic drugs which have acceptable side effects. Such antibody-targeted drugs would be expected to provide either improved therapeutic effects or reduced side effects. Several researchers reported successful conjugates prepared by direct coupling of drugs to antibodies,6) but this type of conjugate has the drawback that there are only a small number of functional groups
IntroductionA fourth heart sound (S4) is sometimes difficult to differentiate from a third heart sound (S3) in some conditions, such as tachycardia or arrhythmia, because both S3 and S4 are perceived as a low-pitched sound and can be distinguished mainly based on the timing in the cardiac cycle [1]. We report a case with hypertrophic cardiomyopathy and Wenckebach second-degree atrioventricular block, in which the S4 was initially misdiagnosed as an S3 on auscultation and later confirmed using a phonocardiogram with an apexcardiogram.
Case reportA 77-year-old man with nonobstructive hypertrophic cardiomyopathy underwent phonocardiography in Matsushita Memorial Hospital. Wenckebach second-degree atrioventricular block had developed several years earlier, but he had been doing well without any symptoms or cardiovascular events. The patient had dyslipidemia and Dubin-Johnson syndrome. His mother reportedly had left ventricular hypertrophy. Medications included mexiletine hydrochloride, warfarin potassium, diltiazem hydrochloride, rebamipide, and pravastatin sodium.On examination, the blood pressure was 140/70 mmHg and the pulse was irregular, with a rate of 78 beats per minute. First heart sound (S1) and second heart sound (S2) were normal with no murmurs. An S4 was faintly audible at the apex in the left lateral decubitus position. Interestingly, other additional heart sounds during early diastole were alternately heard best at the apex, but also at the right and left sternal borders. A presumed diagnosis of S3 was made. The remainder of the examination was normal. An electrocardiogram showed normal sinus rhythm with a rate of 75 beats per minute, right axis deviation, ST-T changes, and isolated premature ventricular contractions; progressively increased PR intervals, sometimes followed by a dropped QRS, were diagnostic of Wenckebach second-degree atrioventricular block that was unchanged from previous findings.A phonocardiogram with microphones placed at the second right sternal border and the apex in the left lateral decubitus A B S T R A C T A third heart sound (S3) and a fourth heart sound (S4) are similarly perceived as low-pitched sounds and can be difficult to distinguish in some conditions, such as tachycardia or arrhythmia. We report a case with hypertrophic cardiomyopathy and Wenckebach second-degree atrioventricular block, in which the S4 was initially misdiagnosed as an S3 on auscultation and later confirmed using a phonocardiogram with an apexcardiogram. Interestingly, the amplitude of the S4 dynamically and regularly fluctuated in proportion to the interval between the S4 and the preceding ventricular contraction. These findings were associated with transmitral inflow patterns assessed by Doppler echocardiography, highlighting the importance of not only transmitral A but also E waves for the amplitude of S4 in patients with arrhythmias.
We have developed a simple and sensitive chemiluminescence-linked immunoassay (CLIA) for determining mumps virus antibodies. Luminol molecules were used as markers, and polystyrene balls were used as antigen carriers. The CLIA was compared with an enzyme-linked fluorescence assay and a hemagglutination inhibition test on a total of 40 serum specimens obtained from 29 donors with natural infection or vaccination. There was good correlation between the three methods, and the sensitivity of the CLIA was about 10 times higher than that of the hemagglutination inhibition test, although it was slightly inferior to that of the enzyme-linked fluorescence assay. Moreover, the time course of light emission from the labeled antibody was rapid, and therefore in the CLIA the quantitation of the marker takes only a short time.
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