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Biomedical subjects

S Greer

Publications and source records attributed to S Greer.

At least 55 records · Page 3Linked to original sources

Successful treatment of idiopathic secretory diarrhea of infancy with the somatostatin analogue SMS 201-995.

The somatostatin analogue SMS 201-995 has been reported to be effective in treating adult secretory diarrhea due to vasoactive intestinal polypeptidoma. We report the effectiveness of this drug in treating severe refractory secretory diarrhea of uncertain etiology in an infant. The patient developed diarrhea within the first few days of life, with mean stool output of 250 ml/kg.day (expected 10 ml/kg.day). Small bowel biopsy showed mild focal enteritis. Serum levels of known gastrointestinal secretagogues were normal. No tumor was detected. Diarrhea was not adequately controlled by various drug treatments. Addition of subcutaneous SMS 201-995 produced a significant sustained decrease in stool output to 80-100 ml/kg.day. During SMS 201-995 treatment, no metabolic, hormonal, or growth abnormalities were noted. SMS 201-995 was discontinued after 9 mo because of patient irritability. Stool output rose immediately to 173 ml/kg.day, and remained stable for 6 mo. It is concluded that SMS 201-995 was a safe and effective treatment in this single childhood case of severe idiopathic secretory diarrhea.

Antidiarrheals↗

Psychological response to cancer diagnosis--I. Correlations with prognostic variables.

A prospective, multidisciplinary study of 168 newly diagnosed patients with early breast cancer and Hodgkin's or non-Hodgkin's lymphoma was conducted. Psychological assessments were conducted at 3 and 12 months following diagnosis and correlated with clinical and pathological variables. There was no statistical association between psychological response to breast cancer and any other prognostic variable measured. In lymphoma patients of both groups there was evidence of greater psychiatric morbidity in those with more advanced disease and those who failed to respond to treatment. However there was also no statistical association between any cognitive response category and known prognostic variables. There was no evidence that the patient's gender or type of tumour affected their overall mental adjustment to cancer and the effect described in breast cancer may apply to all types of malignant disease.

Adaptation, Psychological↗

Development of a questionnaire measure of adjustment to cancer: the MAC scale.

This paper describes the development of a self-rating scale to measure adjustment to cancer. The Mental Adjustment to Cancer (MAC) Scale has been completed by 235 patients with various types and stages of cancer. It is easily understood by, and acceptable to, patients. Data relating to reliability and internal consistency indicate that the MAC scale is a valuable research tool for clinical studies of patients' psychological adjustment to cancer.

Adaptation, Psychological↗

Potentiation of halogenated pyrimidine radiosensitizers in human carcinoma cells by beta-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran- 5,6-dione), a novel DNA repair inhibitor.

3,4-Dihydro-2,2-dimethyl-2H-naptho[1,2,-b]pyran-5,6-dione (beta-lapachone) is a novel DNA repair inhibitor. It was tested for synergistic X-ray-induced lethality in combination with several halogenated pyrimidine radiosensitizers. Logarithmic-phase growing human epidermoid laryngeal carcinoma (HEp-2) cells were allowed to incorporate pyrimidine analogues for 48 h (approximately two cell doublings) and then were X-irradiated and subjected to various posttreatments. beta-Lapachone synergistically increased the dose enhancement ratios (DERs) of all analogues screened, with the exception of the 2'-chloro derivative of 5-bromodeoxyuridine. For example, following 5-bromodeoxycytidine sensitization an X-ray DER value of 1.87 +/- 0.04 at 1% survival was increased to 3.51 +/- 0.42 due to a 4-h post-X-irradiation exposure to 4 microM beta-lapachone. Do and Dq values for halogenated pyrimidine-sensitized human epidermoid laryngeal carcinoma cells were decreased 1.4- to 5.4-fold and 1.4- to 4.0-fold, respectively. beta-Lapachone had little effect upon the cytotoxicities of unirradiated human epidermoid laryngeal carcinoma cells whether or not they were previously exposed to any of the halogenated pyrimidine radiosensitizers. beta-Lapachone treatment following X-irradiation of cells that had not incorporated a pyrimidine analogue exhibited DER values of 1.38 +/- 0.05 and 1.40 +/- 0.01 at 10 and 1% survival levels, respectively. beta-Lapachone enhanced the radiosensitization of deoxycytidine analogues to a greater extent than the structurally related deoxyuridine analogues. Greater DERs and lower Do and Dq values were found for deoxycytidine than for deoxyuridine analogue radiosensitizers following beta-lapachone treatment. This agent may improve presently used radiation therapies and enhance proposed strategies which utilize deoxycytidine analogue radiosensitization together with protection of normal tissues by tetrahydrouridine to achieve tumor-selective radiotherapy.

Bromodeoxycytidine↗

Beta-blocker therapy for the Wolff-Parkinson-White syndrome.

Two types of arrhythmias are associated with the Wolff-Parkinson-White syndrome: those in which the accessory pathway is a required part of the reentrant circuit, e.g., orthodromic atrioventricular reciprocating tachycardia, and those that conduct over the accessory pathway but do not require its activation for maintenance of tachycardia, e.g., atrial flutter/fibrillation. Increased sympathetic tone shortens the refractoriness of atrial and ventricular tissue; however, conduction in the atrium and ventricle is not considered the limiting factor for maintenance of atrioventricular reciprocating tachycardia or conduction over the accessory pathway in atrial arrhythmias. Intravenous beta-adrenergic blockers given to patients in the resting state have a minimal to moderate effect in depressing atrioventricular nodal conduction, but have little or no effect on accessory pathway refractoriness or conduction in most patients. In patients presenting with atrioventricular reentry, intravenous administration of beta-adrenergic blocking drugs often is not effective to terminate tachycardia. However, long-term oral therapy with these agents may be beneficial, especially in patients in whom enhanced sympathetic tone is responsible for the initiation or maintenance of tachycardia.

Adrenergic beta-Antagonists↗

Protective, tumor-selective dual pathway activation of 5-fluoro-2'-deoxycytidine provided by tetrahydrouridine in mice bearing mammary adenocarcinoma-755.

Treatment of C57BL X DBA/2 F (hereafter called BD2F) mice bearing ascitic mammary adenocarcinoma-755 (ADC-755) with [3H]-5-fluoro-2'-deoxycytidine ([3H]FdCyd) plus tetrahydrouridine (H4Urd) resulted in antimetabolite pool sizes indicative of a tumor-selective, dual pathway metabolism of FdCyd via both cytidine deaminase and deoxycytidine kinase. In contrast to the high levels of all RNA- and DNA-level antimetabolites (as assayed by high performance liquid chromatography) derived from FdCyd found in tumor tissue, normal tissues (bone marrow, intestine, liver, and spleen) and serum metabolized FdCyd to only a small extent following FdCyd plus H4Urd treatment. RNA-level antimetabolite pools and 5-fluoro-2'-deoxyuridine (FdUrd) were generally 100-fold lower in normal than in tumor tissue, and 5-fluoro-2'-deoxyuridylate was 10- to 15-fold lower in normal than in tumor tissue. The use of [3H]FdUrd, on the other hand, resulted in the formation of higher levels (10- to 40-fold) of DNA- and RNA-level antimetabolites in normal tissue and lower levels (1/8) of 5-fluoro-2'-deoxyuridylate in tumor tissue. Both [3H]FdCyd plus H4Urd and [3H]FdUrd were utilized at their optimal drug doses. FdUrd- and FdCyd-derived metabolic products incorporated into the RNA and DNA of normal and tumor tissue of BD2F mice bearing ADC-755 were also examined. The drug combination [3H]FdCyd plus H4Urd resulted in the selective incorporation of antimetabolites into tumor RNA and DNA; only a very small extent of antimetabolites incorporated into normal tissue RNA and DNA. FdCyd was incorporated 5- to 10-fold greater in tumor than intestine, liver, or spleen following FdCyd plus H4Urd administration. FdCyd incorporation was 190-fold greater in tumor than in bone marrow. Mice bearing ADC-755 treated with [3H]-FdUrd resulted in only marginal selectivity in terms of antimetabolite incorporation in tumor tissue. Deoxycytidylate and cytidine deaminase enzyme assays have confirmed that H4Urd administration effectively inhibited normal cytidine deaminase activities, while only weakly inhibiting the elevated levels found in tumor tissue. Thymidine kinase, deoxycytidine kinase, deoxycytidylate deaminase, and cytidine deaminase have been shown previously to be significantly elevated in the mouse tumor model used; these enzymatic elevations are also characteristic of many human tumors. Treatment with FdCyd plus H4Urd resulted in 17 of 30 cures against ADC-755 compared to 4 of 20 and 0 of 20 for 5-fluorouracil and 5-fluoro-2'-deoxyuridine treatments, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Tumor-selective metabolism of 5-fluoro-2'-deoxycytidine coadministered with tetrahydrouridine compared to 5-fluorouracil in mice bearing Lewis lung carcinoma.

The metabolic products formed and incorporated into the nucleic acids (RNA and DNA) of mice bearing Lewis lung carcinoma (LLC) following optimal doses of 5-fluorouracil (FUra), 5-fluoro-2'-deoxyuridine (FdUrd), and 5-fluoro-2'-deoxycytidine (FdCyd) coadministered with tetrahydrouridine (H4Urd), a potent inhibitor of cytidine deaminase, were examined. Treatment with FdCyd plus H4Urd resulted in a tumor-selective incorporation and formation of antimetabolites compared to either FUra or FdUrd treatments. Between 45- and greater than 5400-fold higher levels of the potent thymidylate synthetase inhibitor, 5-fluoro-2'-deoxyuridylate (FdUMP), were formed in tumor than in any of the normal tissues analyzed. RNA-level antimetabolites (FUra, 5-fluorouridine, and 5-fluorouridylate) were also between 3 and greater than 990-fold higher in tumor compared to normal tissue following FdCyd plus H4Urd administration. DNA-level antimetabolites (FdCyd, 5-fluorodeoxycytidylate, FdUrd, and FdUMP) were from 2- to 6-fold higher in tumor compared to normal tissue. FUra and FdUrd treatments resulted in between 3 and greater than 1300-fold higher RNA-level antimetabolites and from 4 to greater than 1020-fold higher FdUMP pools in normal tissues than FdCyd plus H4Urd treatment. DNA-level antimetabolites were also from 4- to 32-fold higher in normal tissues following optimal doses of FUra or FdUrd. In tumor tissue, optimal doses of FUra or FdUrd resulted in lower (a) FdUMP levels (5- to 2-fold), (b) RNA-level antimetabolites (6- to 3-fold), and (c) DNA-level antimetabolites (10- to 4-fold) compared to an optimal dosage of FdCyd plus H4Urd. In serum, the administration of H4Urd resulted in the protection of FdCyd from systemic catabolism, unlike that found with FUra or FdUrd. Substantial levels of FdUMP, FUrd, and FUMP were noted in serum following FUra or FdUrd treatment. The formation of di- and triphosphate antimetabolite pools and the incorporation of antimetabolites into the RNA and DNA of normal and tumor tissues demonstrated trends similar to those mentioned above with nucleoside, mononucleotide, and free base pools. H4Urd treatment of 25 mg/kg did not affect the elevated levels of deoxycytidine kinase or deoxycytidylate deaminase in LLC tumor tissue or the low levels found in normal tissue. A critical feature of this chemotherapeutic strategy using FdCyd plus H4Urd was that the elevated level of cytidine deaminase in LLC tumor tissue was inhibited less than 10% by the administration of 25 mg/kg H4Urd, whereas deoxycytidine deaminase activities in normal tissues (including bone marrow and intestine) were inhibited greater than 93%.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.

The efficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon. Seventy-six patients received active medication and 77 received a placebo. There were 20 dropouts (6 in the active group and 14 in the placebo group) during the study because of insufficient efficacy. After 6 wk of therapy, 48 of the 76 patients (63%) receiving 5-aminosalicylic acid were considered to be "much improved" by the study physician compared to 22 of the 77 patients (29%) on placebo (p = 0.001). A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mean disease activity index declined 55% for patients on 5-aminosalicylic acid and 24% for patients on placebo (p = 0.0001). Analysis of subgroups indicated that patients most likely to respond were those with disease confined to the 20-40 cm from the anus. Response was not affected by concurrent sulfasalazine, but patients requiring concurrent oral steroids had a diminished response. Rapid onset of efficacy was shown by a significant reduction in rectal bleeding within 3 days of treatment initiation. 5-Aminosalicylic acid enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon.

Adult↗

Mental adjustment to cancer: its measurement and prognostic importance.

Can the mental adjustment of patients to cancer influence the course of their disease? This question is considered in a critical review of relevant studies. Salient problems in this field of research are identified and basic methodological requirements outlined. The few systematic, prospective investigations which meet these requirements show evidence for an association between mental adjustment to cancer and subsequent outcome in patients with 'early'--ie non-metastatic disease. The evidence, however, should be regarded as provisional rather than conclusive. A definitive answer will require further carefully controlled long-term follow-up studies. In such studies, a crucial methodological issue is the measurement of mental adjustment to cancer. Hitherto, this has been based solely on clinical assessments. The development of a new measure of mental adjustment to cancer is reported. The MAC scale is a 40-item self-rating questionnaire. Initial results based on a study of 235 patients with a variety of cancers indicate that the scale is acceptable to patients, easy to administer in busy oncology clinics, reliable and stable over time. Its validity as measured by spouses' ratings appears satisfactory. Further evaluation is required. These preliminary results suggest that the MAC scale is a suitable, easily replicable method of measuring adjustment to cancer in studies of large numbers of patients.

Adaptation, Psychological↗

Adjuvant psychological therapy for patients with cancer.

Cancer-related psychosocial morbidity has been documented in a substantial minority of patients. In some patients, such morbidity persists for many years even when they are free of disease. Consequently, methods of reducing psychosocial morbidity by psychological treatment should be investigated. We describe Adjuvant Psychological Therapy (APT)--a brief treatment programme designed specifically for patients with cancer. APT is currently being evaluated in a randomized, controlled study at The Royal Marsden Hospital.

Adaptation, Psychological↗

Analysis of 5-fluoro-2'-deoxycytidine and 5-trifluoromethyl-2'-deoxycytidine and their related antimetabolites by high-performance liquid chromatography.

An isocratic, ion-paired, reversed-phase high-performance liquid chromatography technique for the quantitative determination of 5-fluoro-2'-deoxycytidine (FdCyd) and 5-trifluoromethyl-2'-deoxycytidine (F3methyldCyd) and their related antimetabolites is described. Extraction and purification of these compounds from DNA, RNA, and free pools is reviewed diagrammatically. Total analysis time including quantitation of DNA and RNA primary constituents is 45 min. Average combined recoveries for prodrugs and antimetabolites is above 90% with standard deviations of 0.07 and 0.58 and average precisions of 5.51 and 8.30% for FdCyd and F3methyldCyd, respectively. Average coefficients of variation were 3.8 +/- 0.5% for FdCyd and 7.7 +/- 1.0% for F3methyldCyd. Limits of detection were approximately 1 pmol for unlabelled prodrugs and antimetabolites. FdCyd, when generally tritiated with a specific activity of 18 Ci/mmol, was detected in the 5 X 10(-15)-20 X 10(-15) mol (fmol) range depending on sample condition.

Buffers↗

Glutathione reductase from Escherichia coli: cloning and sequence analysis of the gene and relationship to other flavoprotein disulfide oxidoreductases.

A glutathione reductase negative strain of Escherichia coli K-12 was isolated as a thermoresistant survivor when a gor::MuctsAp lysogen was subjected to elevated temperature. It was found that in addition to being ampicillin sensitive this mutant was hypersensitive to arsenate, which may be connected with the fact that the gor gene maps between 77 and 78 min on the E. coli genome, close to the pit locus encoding the major arsenate transport system of E. coli. A derivative of this mutant was used as the recipient in a screen of the Clarke and Carbon hybrid plasmid bank of E. coli DNA. A plasmid, pGR, was isolated that encodes both an arsenate-resistance element and glutathione reductase. Restriction mapping of this plasmid showed that the insert DNA is approximately 10 kilobase pairs in length, and a fragment of the gor gene was identified that allowed the gor gene to be accurately mapped on pGR by a combination of restriction analysis and Southern blotting. The DNA sequence of the gor gene was determined and found to encode a protein of 450 amino acid residues. The glutathione reductase of E. coli is very homologous to the human enzyme and is also related (though less closely) to other flavoprotein disulfide oxidoreductases whose sequences are available. These enzymes have retained a common mechanism while evolving different specificities.

Amino Acid Sequence↗