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Biomedical subjects

S M Grunberg

Publications and source records attributed to S M Grunberg.

80 records · Page 5Linked to original sources

Comparison of the antiemetic effect of high-dose intravenous metoclopramide and high-dose intravenous haloperidol in a randomized double-blind crossover study.

Metoclopramide is an effective antiemetic for cisplatin-induced vomiting when given in parenteral high-dose regimens but not oral low-dose regimens. Metoclopramide was compared to haloperidol, also given in a high-dose parenteral regimen. Patients received two cycles of cisplatin at a dose greater than or equal to 70 mg/m2. Metoclopramide (2 mg/kg intravenous) was given every two hours for five doses beginning one half hour before cisplatin. Haloperidol (3 mg intravenous) was given on the same schedule. A randomized double-blind crossover design was used to control subjective bias and to compare the same patient's experiences. Twenty-eight patients completed both study arms. Excellent control of vomiting was achieved with both drugs. Metoclopramide resulted in 1.92 vomiting episodes (range, 0-5) with 36% having no vomiting. Haloperidol resulted in 3.04 vomiting episodes (range, 0-8) with 20% having no vomiting. Significantly fewer vomiting episodes were noted with metoclopramide rho = .006, paired sign test). However, responses to the two drugs were well correlated (Spearman's rho = .39, P = .03). Metoclopramide and haloperidol are both excellent antiemetics when given in sufficient dosage by an effective route. Metoclopramide does show a mild advantage. However, the positive correlation in response to these agents suggests a common mechanism of action. The ability to identify related antiemetics will be useful in the design of rational combination antiemetic therapy.

Adult↗

A phase II study of recombinant alpha interferon in patients with recurrent or metastatic breast cancer.

Thirty-three patients with advanced breast cancer were treated with a recombinant alpha interferon (rIFN-alpha 2). All patients were ambulatory (performance status greater than or equal to 50 Karnofsky scale) and almost all had received previous chemotherapy. Large intravenous dosages of 30 to 50 X 10(6) IU/m2 were given for five consecutive days every two to three weeks to 22 patients and smaller subcutaneous dosage of 2 X 10(6) IU/m2 three times a week to 11 patients. No complete or partial responses were seen. Two patients had stable disease and the remainder progressed. Flu-like syndromes were seen in all patients. Nausea, vomiting, and anorexia were frequent. Hypotension and confusion were noted in six and five patients, respectively. Life-threatening leukopenia was noted in two patients receiving intravenous dosage and thrombocytopenia was noted in one; no sepsis or bleeding complications were noted. In this study, a highly purified and biologically active rIFN-alpha 2 was not associated with activity in previously treated women with metastatic breast cancer.

Adult↗

Enzyme action at 3' termini of ionizing radiation-induced DNA strand breaks.

gamma-Irradiation of DNA in vitro produces two types of single strand breaks. Both types of strand breaks contain 5'-phosphate DNA termini. Some strand breaks contain 3'-phosphate termini, some contain 3'-phosphoglycolate termini (Henner, W.D., Rodriguez, L.O., Hecht, S. M., and Haseltine, W. A. (1983) J. Biol. Chem. 258, 711-713). We have studied the ability of prokaryotic enzymes of DNA metabolism to act at each of these types of gamma-ray-induced 3' termini in DNA. Neither strand breaks that terminate with 3'-phosphate nor 3'-phosphoglycolate are substrates for direct ligation by T4 DNA ligase. Neither type of gamma-ray-induced 3' terminus can be used as a primer for DNA synthesis by either Escherichia coli DNA polymerase or T4 DNA polymerase. The 3'-phosphatase activity of T4 polynucleotide kinase can convert gamma-ray-induced 3'-phosphate but not 3'-phosphoglycolate termini to 3'-hydroxyl termini that can then serve as primers for DNA polymerase. E. coli alkaline phosphatase is also unable to hydrolyze 3'-phosphoglycolate groups. The 3'-5' exonuclease actions of E. coli DNA polymerase I and T4 DNA polymerase do not degrade DNA strands that have either type of gamma-ray-induced 3' terminus. E. coli exonuclease III can hydrolyze DNA with gamma-ray-induced 3'-phosphate or 3'-phosphoglycolate termini or with DNase I-induced 3'-hydroxyl termini. The initial action of exonuclease III at 3' termini of ionizing radiation-induced DNA fragments is to remove the 3' terminal phosphate or phosphoglycolate to yield a fragment of the same nucleotide length that has a 3'-hydroxyl terminus. These results suggest that repair of ionizing radiation-induced strand breaks may proceed via the sequential action of exonuclease, DNA polymerase, and DNA ligase. The possible role of exonuclease III in repair of gamma-radiation-induced strand breaks is discussed.

Alkaline Phosphatase↗

Immunological effects of recombinant interferon-alpha 2 in cancer patients.

Fifteen patients with various types of cancer, resistant to conventional therapy, were entered into a phase I trial of pure interferon-alpha 2 (IFN-alpha 2) produced by recombinant DNA technology. Groups of patients received either 3, 10, 30, or 50 x 10(6) units (U) of IFN-alpha 2 subcutaneously daily for 4 weeks and were closely followed for possible toxicity. At the higher doses, toxicity was encountered, which led to reduction in the frequency of administration. For immunological testing, peripheral blood mononuclear cells were obtained before treatment on day 1, on day 2, and during the 2nd, 3rd, and 7th weeks of the study. The cells were tested for natural killer (NK) activity, antibody-dependent cellular cytotoxicity (ADCC), monocyte-mediated antibody-dependent cellular cytotoxicity (MMADCC), and spontaneous monocyte-mediated cytotoxicity (SMC). ADCC was augmented at all doses in 9 of 15 patients, 6 of whom exhibited elevated levels by day 2. In direct contrast, MMADCC was decreased in 12 of 14 patients 7-20 days after beginning treatment. SMC was increased on day 2 in 1 of 2 patients given 3 x 10(6) U and in 3 of 4 patients given 10 x 10(6) U. SMC in the other patients given these doses was unchanged on day 2, with no decreases noted. In contrast, SMC was decreased in 2 of 4 patients given 30 x 10(6) U. SMC in the other patients given these doses was unchanged on day 2, with no decreases noted. In contrast, SMC was decreased in 2 of 4 patients given 30 x 10(6) U and in 2 of 3 patients given 50 x 10(6) U. NK cell activity was increased in 2 of 3 patients given 3 x 10(6) U, but was either unchanged or decreased in patients given higher doses. The only exception was an increase found in a patient given 50 x 10(6) U, whose renal cell carcinoma responded significantly to treatment. Data on NK and SMC from a phase II study of breast cancer treated daily with 3 x 10(6) U IFN-alpha 2 support our phase I observations. NK-cell activity was increased on day 2 in 3 of 8 patients, and SMC increased in 2 of 8 patients. As in the phase I study, no decreases in these functions occurred. In summary, for those responses that were dose dependent, such as NK and SMC, lower doses of recombinant IFN-alpha 2 (3 x 10(6) and possibly 10 x 10(6) U) may be more effective in increasing these antitumor activities than are higher doses.

Adult↗

Sites and structure of gamma radiation-induced DNA strand breaks.

DNA fragments of defined sequence were used to study DNA strand breakage by gamma radiation in doses ranging from 2,500 to 20,000 rads. The amount of radiation-induced DNA breakage is linearly dose-dependent, and strand scission events occur uniformly at all nucleotide sites, regardless of sequence. The 5'-terminal group at points of breakage is a simple phosphoryl moiety. Two types of radiation-induced 3' termini were identified. One species of 3' terminus is a simple phosphoryl group. The other species of 3' terminus is neither a hydroxyl nor a phosphoryl group. A model for radiation-induced DNA strand scission that involves destruction of the deoxyribose moiety is presented. Similarities among DNA strand scission events created by gamma radiation, ferrous ion, doxorubicin, and bleomycin are discussed.

DNA, Bacterial↗

Development of Cushing's syndrome and virilization after presentation of a nonfunctioning adrenocortical carcinoma.

Adrenocortical carcinoma is traditionally divided into functioning and nonfunctioning tumors. However, a case is presented of a 50-year-old woman with a clinically nonfunctioning adrenocortical carcinoma who later developed a Cushingoid appearance and symptoms of virilization with laboratory evidence of marked steroid hormone hypersecretion. The metabolic behavior and the rationale for division of these tumors into two categories (functioning and nonfunctioning) are discussed. It is suggested that such a division may be misleading and may not reflect the true state of the tumors.

Adrenal Gland Neoplasms↗

Use of an indicator sequence of human DNA to study DNA damage by methylbis(2-chloroethyl)amine.

A highly reiterated sequence of human DNA was used to determine the sites of modification of DNA caused by the anti-tumor drug methylbis(2-chloroethyl)amine (HN2, mechlorethamine, nitrogen mustard) upon treatment of cells in culture and of purified DNA. The lengths of the breakage products of the DNA treated with HN2 were compared to the lengths of DNA scission products produced by chemical reactions used for DNA sequence determination. HN2 was found to create alkali-labile lesions at positions of guanine. The distribution of the guanine modifications was the same for DNA extracted from cells treated with HN2 and for purified DNA treated with HN2. However, the extent of damage was at least 2-fold greater when purified DNA was used as the substrate. Several nitrogen mustard analogues also produced alkali-labile lesions at positions of guanine.

Alkylating Agents↗

High dose intensity of cisplatin and etoposide in adenocarcinoma of unknown primary.

Adenocarcinoma of unknown primary (AUP) has generally a poor prognosis. Previous studies have suggested that Cisplatin and Etoposide have activity in AUP. The aim of this study was to determine if dose intensification of this combination would result in increased efficacy. Each 28 day cycle consisted of Cisplatin 100 mg/m2 given on Day 1 and 8 with Etoposide 80 mg/m2 given on day 1, 2, 8 and 9. Sixteen patients (Pts) with no prior chemotherapy were accrued to this study. Predominant sites of disease were lung, liver, and bone. BHCG and AFP were not elevated. One complete remission was seen in a patient with a mediastinal mass (duration of remission = 59 weeks). Two other patients had a partial response. Overall response rate was 19%. Moderate to severe renal toxicity was recorded in 8 patients, with neuro- and ototoxicities in 2 patients each. Severe granulocytopenia occurred in 8 patients, and one patient died of congestive heart failure on day 1 of cycle 2. This excessive toxicity, without enhanced efficacy does not encourage a more extensive empiric trial by this dose schedule in the treatment of AUP.

Adenocarcinoma↗