Biomedical subjects
Publications and source records attributed to J E Crook.
Genetic factors are important in Alzheimer disease (AD) and Parkinson disease but have not been well characterized in Lewy body dementia (LBD). The authors obtained family history in patients from an autopsy series of AD and LBD and in living healthy controls. A family history of dementia was more common in both LBD and AD compared with controls, suggesting that genetic factors are as important in LBD as they are in AD.
Monoclonal antibody CO17-1A was radiolabeled with 90Y by five bifunctional chelate techniques. Radiation absorbed dose estimates for normal organs and tumor were calculated for each preparation based on timed tissue distribution studies in nude mice bearing SW 948 human colorectal carcinoma xenografts. The cyclic DTPA anhydride technique was inferior to the four other techniques studied. Data for SCN-Bz-DTPA and SCN-Bz-Mx-DTPA, which were conjugated to epsilon-lysyl amino groups, were similar to those for NH2-Bz-DTPA and NH2-Bz-Mx-DTPA, which were conjugated site specifically to oligosaccharides.
Monoclonal antibody CO17-1A, which has specificity for colorectal and pancreatic carcinomas, was radiolabeled with the pure beta emitter, 90Y, by either the cyclic diethylenetriaminepentaacetic acid (DTPA) anhydride technique or by a site-specific bifunctional chelate technique using 1-(p-aminobenzyl)DTPA (p-NH2-Bz-DTPA). Female nude mice bearing SW 948 human colorectal carcinoma xenografts were given injections i.v. of 90Y-labeled monoclonal antibody CO17-1A at dosages of 100, 150, and 200 muCi/25 g body weight. Unlabeled CO17-1A (100 micrograms/25 g body weight) was coadministered. In animals receiving 90Y-CO17-1A prepared by the cyclic DTPA anhydride technique, tumor volume was unchanged from base line at a dose of 200 microCi/25 g. As the dosage of 90Y-CO17-1A increased, the rate of tumor growth decreased, but all experimental animals in this group died between 14 and 21 days. In contrast, CO17-1A radiolabeled with 90Y by the site-specific p-NH2-Bz-DTPA bifunctional chelate technique produced a maximum tumor volume reduction of 87% in the 200 microCi/25 g group by day 15, and no deaths were noted in any of the 90Y-CO17-1A-treated groups for 71 days. Dose-response curves again showed increased tumoricidal effects with increased dosages of 90Y-CO17-1A. S-2-(3-Aminopropylamino)ethylphosphorothioic acid, commonly known as WR-2721, is a radioprotective drug which has been shown to protect against bone marrow depression in irradiated humans. No protection was observed when WR-2721 was used as an adjunct to treatment with 90Y-CO17-1A prepared by either the cyclic DTPA anhydride technique or the site-specific p-NH2-Bz-DTPA technique. When the site-specific p-NH2-Bz-DTPA technique was used, the reduction in WBC and hemoglobin levels correlated with increasing bone marrow toxicity at higher doses. We conclude that CO17-1A labeled with 90Y via the site-specific p-NH2-Bz-DTPA technique has potential for radioimmunotherapy of human colorectal carcinoma.
The cotton-top tamarin, Saguinus oedipus, serves as an animal model for the study of human colon cancer. This New World monkey has a high incidence of colitis and colon cancer that develops spontaneously. Evidence suggests that these diseases may be the result of a virally induced immunodeficiency. We have shown that T4+/T8+ cell ratios are significantly altered in tamarins with acute colitis and colon cancers. The T4+/T8+ ratios were 1.50 +/- 0.09, 0.70 +/- 0.05, and 0.48 +/- 0.05 for negative controls, acute colitis, and cancer positive tamarins, respectively. Statistical analysis showed a significant difference (p less than or equal to .0005) between negative controls vs. acute colitis and cancer positive groups.
Diagnosing colon cancer in its early stages would lower the mortality rate. The cotton-top tamarin, Saguinus oedipus, serves as a model for the study of human colon cancer. This New World monkey has a high incidence of colitis and colon cancer. The mouse anti-human monoclonal antibody BR55.2, with specificity for human colon adenocarcinoma, was biotinylated. Peripheral blood mononuclear cells (PBMC) from animals with colon cancer were fluorescently stained with the biotinylated BR55.2. These results showed the cross-reactivity of mouse anti-human colon cancer monoclonal antibody to the PBMC of cancerous tamarins. Antibodies from either cancerous or chronic colitis tamarins were also biotinylated. Fluorescently labeled cells were detected when PBMC from cancerous tamarins were incubated with biotinylated antibodies from cancerous tamarins. Cytofluorographic analysis also showed a significant 4.5-fold difference in the percentage of fluorescently labeled PBMC between cancerous and chronic colitis tamarins when stained with biotinylated antibodies from cancerous tamarins. DNA flow cytometry analysis showed that PBMC from cancerous tamarins have a higher percentage of aneuploid cells than PBMC from chronic colitis tamarins.
Monoclonal antibody CO17-1A was radiolabeled with 90Y using the cyclic DTPA anhydride technique and administered intravenously to athymic nude mice bearing SW 948 human colorectal carcinomas. The tumor specificity of 90Y-CO17-1A was improved by coadministration of 100 micrograms of the unlabeled antibody per animal and by purification using HPLC instead of column gel filtration chromatography. Absorbed radiation dose estimates for 90Y-CO17-1A were calculated. The radiation dose to the bone marrow will limit the amount of 90Y-CO17-1A that can be administered for cancer therapy.
Monoclonal antibody 17-1A, which has specificity for colorectal carcinoma, was labeled with 90Y (10-20% radiolabeling yield). Tissue distribution studies in tumor-bearing nude mice were carried out. 90Y-labeled 17-1A showed good uptake in the SW 948 colon carcinoma cell line. However, 90Y-labeled A5C3, a monoclonal antihepatitis virus antibody studied as a control, showed similar uptake in this tumor. Neither antibody was taken up well by a WM-9 melanoma. It is believed that the loss of specificity observed is due to the low specific activity of the 90Y-labeled monoclonal antibody preparations used. This hypothesis is supported by radioimmunoassay data.
A 70-year-old man with classic severe idiopathic orthostatic hypotension received three different indomethacin dose regimens. Baseline urinary prostaglandin concentrations were modestly elevated. Although indomethacin greatly lowered prostaglandin production, no sustained improvement in blood pressure or symptoms occurred. It is proposed that the interindividual variations in vascular reactivity and circulating prostaglandin levels may account for the beneficial responses to indomethacin of some patients and the modest responses of others.
A patient with recurrent, life-threatening water intoxication secondary to compulsive water drinking is described. This patient responded well to nearly 1 g of propranolol daily with a decrease in her drinking behavior, reduced sensation of thirst, and a reduction in her delusional thinking. The rationale for the choice of propranolol with this patient is reviewed.
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We have presented two cases of agranulocytosis occurring in patients receiving a combination antiarrhythmic regimen. As multiple drug therapy for ventricular arrhythmias becomes more commonplace, increased scrutiny should be given to agents chosen, in an effort to prevent any possible adverse interactions. When future cases are encountered, the acetylator pheontype should be determined. This information would aid in assessing the predicative value of the acetylator phenotype in the development of agranulocytosis. Due to the inherent danger, neither patient was rechallenged with procainamide nor phenytoin.
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Drug interactions with antihypertensive drugs can be either beneficial or hazardous. The hazardous interactions are relatively infrequent but must be shown so they can be avoided. Those of most importance involve interaction with guanethidine-type agents and tricyclic antidepressants, amphetamine-type anorexiants or phenolpropanolamine-type common cold remedies; combined use of potassium retaining diuretics with potassium supplements; and incautious use of diuretics with cardiac glycosides. The beneficial interactions are the basis for modern antihypertensive therapy and can be of major help if logically applied to therapeutic problems.
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