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Biomedical subjects

E Frei

Publications and source records attributed to E Frei.

At least 217 records · Page 12Linked to original sources
PubMed1987

Could N-nitrosamino phosphates be transport forms of activated N-nitrosamines?

The stability of N-nitroso-N-methylamine-N-ethyl phosphate (NMEP) and N-nitroso-N-ethylamine-N-ethyl phosphate (NEEP) was studied in rat serum and in rat liver homogenate and found to be sufficiently high for the phosphates to be transported in vivo. In liver homogenates, the cleavage was more efficient, and a higher phosphatase activity was found in liver microsomal and cytosolic fractions than in serum. The substances exert a distinct activity in the Salmonella typhimurium mutagenicity test.

Alkaline Phosphatase↗
PubMed1986

Neuroblastoma in adults. Three case reports and a review of the literature.

Three adult patients with neuroblastoma have been treated recently at the Dana-Farber Cancer Institute. One adult neuroblastoma patient experienced two distinct paraneoplastic syndromes that have not been reported previously in association with neuroblastoma. The clinical data on our three patients are presented in detail and the important features of 27 cases that have been described in the literature are summarized. This study suggests that the distribution of primary neuroblastoma sites in adults is similar to that seen in pediatric cases but that the natural history of the disease may be longer. Furthermore, this study suggests that neuroblastoma in adults may be less sensitive to chemotherapy than is the childhood disease.

Adult↗
PubMed1986

Determination of DNA single strand breaks and selective DNA amplification by N-nitrodimethylamine and analogs, and estimation of the indicator cells' metabolic capacities.

N-nitrodimethylamine is metabolized oxidatively to N-nitrohydroxymethylmethylamine, which decomposes to yield formaldehyde and N-nitromethylamine. All four compounds and N-nitromethylamine were tested for their ability to induce DNA single strand breaks in hepatocytes and in SV 40-transformed Chinese hamster embryo cell lines. Only the two monoalkylnitramines were positive. They induced single strand breaks in hepatocytes, but were not effective in the other cells. Formaldehyde and N-nitrohydroxymethylmethylamine were toxic to the cells. None of the compounds tested was able to induce selective DNA amplification in the two transformed cell lines. Enzymes involved in drug metabolism were assayed in the hamster cell lines. The activity of UDP-glucuronosyltransferase and cytosolic epoxide hydrolase were not detectable. N-nitrodimethylamine demethylation was low. The content of reduced glutathione and the activities of glutathione transferase and membrane bound epoxide hydrolase were comparable to values obtained in the rat liver.

Animals↗
PubMed1986

Pharmacokinetics of dibromodulcitol in humans: a phase I study.

A combined clinical and pharmacokinetic phase I study of the substituted hexitol dibromodulcitol (DBD), administered as a single oral monthly dose, has been performed. Twenty-three patients with advanced neoplasms received DBD doses ranging from 600 to 1,800 mg/m2 body surface area (BSA). The dose-limiting toxicity was myelosuppression, with both significant granulocytopenia and thrombocytopenia occurring at dose levels of 1,500 to 1,800 mg/m2. The average pharmacokinetic parameters for DBD, calculated on the basis of a one-compartment model with first-order absorption and elimination, include the elimination constant, .005 +/- .002/min; absorption constant, .012 +/- .009/min; and an apparent volume of distribution, 1.03 +/- .4 L/kg. The area under the drug concentration curve (AUC) and the peak drug level (Cmax) were linearly related to the dose administered (P less than .001). The mean AUC was 18.7 +/- 6.1 mmol/L min, and the mean Cmax was 47.1 +/- 16.8 mumol/L when normalized to a DBD dose of 1 gm/m2. The elimination constant was significantly reduced in patients with abnormal hepatic function (P less than .01). The elimination constant was not correlated with renal function. The half-life of DBD in plasma (158 minutes) was considerably shorter than the four-to eight-hour half-life of total radioactivity in plasma measured by previous investigators following the administration of radiolabeled DBD.

Absorption↗
PubMed1986

Pathology of surgery after induction chemotherapy: an analysis of resectability and locoregional control.

At the Dana-Farber Cancer Institute Head and Neck Cancer Clinic, 114 previously untreated patients with advanced squamous cell carcinoma of the head and neck (17% stage III; 83% stage IV) were managed with induction chemotherapy using cis-platinum, bleomycin, and methotrexate, followed by definitive extirpative surgery and/or radiation therapy. The present report evaluates this group from a surgical and surgical pathology standpoint. The following aspects are evaluated: predictability of, and conversion to, resectability during induction chemotherapy; ease of surgical technique and intraoperative assessment; patterns of pre-op and post-op risks and complications; gross and histopathologic observations of the extent and character of residual primary and nodal disease, particularly after a response to chemotherapy; patterns of locoregional control or failure related to treatment variables. The issues subsequently addressed include: how does chemotherapy affect the operative candidacy and resectability of proposed surgical patients? Could, or should surgery be eliminated in the management of some patients treated with induction chemotherapy? Can less radical surgery be contemplated in patients significantly "downstaged" by prior chemotherapy treatment? Is increased locoregional or distant metastatic control observed in these patients? What is the role of surgery in the responder to chemotherapy?

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Prediction of the optimal timing of bone marrow reinfusion after high dose chemotherapy.

Autologous bone marrow transplantation allows the use of high dose chemotherapy by obviating dose limiting myelosuppression. The pharmacology of high dose chemotherapy has been inadequately explored, yet this information is critical to determine the timing of marrow infusion and assure that engraftment is not compromised. We have used the Salmonella mutagenesis test (SMT) and colony forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte assay to evaluate the optimal time for marrow infusion after therapy with high dose combinations of alkylating agents (Solid Tumor Autologous Marrow Support Program) in seven patients. The SMT is sensitive, rapidly performed, and has been used to detect mutagenic activity in urine following administration of cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea. In parallel, determination of colony forming ability of the patients own bone marrow (colony forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte assay), when cocultured with autologous serum obtained before and after treatment, provided an assay for circulating marrow toxic drugs or metabolites. The onset of mutagenic activity in the SMT and the in vitro appearance of myelotoxicity by autologous serum in the colony forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte assay were concurrent, and these activities returned to base line at the time of marrow infusion (72 h posttreatment). One patient of the seven was excreting mutagens (TA100 strain only) at the time of marrow reinfusion; he developed hepatic venoocclusive disease, and delayed engraftment. These observations suggest that as high dose regimens evolve the SMT may serve as a rapid, sensitive indicator of the circulation and excretion of toxic compounds, and thereby assist in predicting the optimum time of bone marrow reinfusion.

Alkylating Agents↗
PubMed1986

Pharmacokinetics and immediate effects of high-dose carmustine in man.

The pharmacokinetics and acute toxicity of carmustine (BCNU) have been studied in ten patients receiving high-dose combination chemotherapy with cyclophosphamide, cisplatin, and BCNU as treatment for advanced neoplasms. Patients received from 300 to 750 BCNU mg/m2 of body surface area as a 2-hour infusion. The immediate effects of this schedule of BCNU included tachycardia, hypotension, flushing, confusion, nausea, and vomiting. Hypotension was a prominent feature of high-dose BCNU administration. The pharmacokinetics of high-dose BCNU were studied via serial blood samples obtained during and following BCNU infusion. Concentrations of BCNU in total plasma and ultrafiltrable (bioavailable) plasma were determined by high-pressure liquid chromatography with UV detection. Average pharmacokinetic parameters for bioavailable plasma BCNU, calculated on the basis of a one-compartment model, include an elimination constant of 0.031 min-1 and a volume of distribution of 5.1 L/kg. Average clearance of total plasma BCNU is 77.6 ml/kg/min. When corrected to a constant dose of 1 g/m2, the average peak concentration at the end of the infusion was 7.8 microM and the area under the curve was 538 microM X min. Plasma BCNU was largely (77%) protein bound. The distribution, clearance, and protein binding of high-dose BCNU were similar to those reported for standard-dose BCNU.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Alkylating agents: in vitro studies of cross-resistance patterns in human cell lines.

The alkylating agents represent one of the most important classes of antitumor agents and play a major role in combination with other agents in the curative chemotherapy of selected human cancers. By repeatedly exposing cells to escalating doses of an alkylating agent, we have developed four human tumor cell lines which are relatively stably resistant to the drug with which the culture was treated. The response of these cell lines to a variety of alkylating agents was compared to the response of the parent cell lines to the same drug. The Raji/HN2 line was 7-fold resistant to nitrogen mustard and about 3-fold resistant to 4-hydroxyperoxycyclophosphamide, but it was not resistant to N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), melphalan (MEL), busulfan, trimethyleneiminethiophosphoramide, 4-hydroperoxyifosfamide, or cisplatin [cis-diamminedichloroplatinum(II)] (CDDP). The Raji/BCNU line was 5.3-fold resistant to BCNU and 4-fold resistant to both MEL and CDDP. The Raji/CP line was 7-fold resistant to CDDP and 3-fold resistant to both nitrogen mustard and BCNU, but it was not resistant to busulfan, trimethyleneiminethiophosphoramide, or 4-hydroperoxyifosfamide. The SCC-25/CP line, which was 12-fold resistant to CDDP, was 5-fold resistant to MEL and 3-fold resistant to 4-hydroxyperoxycyclophosphamide. The SCC-25/CP line was almost 24-fold resistant to methotrexate after 30-min treatment and about 7-fold resistant to methotrexate after continuous treatment. None of the other cell lines was resistant to methotrexate. The survival of SCC-25 and SCC-25/CP cells exposed to several antineoplastic agents was examined over several logs of survival. The SCC-25/CP cells are highly resistant to CDDP; the ratio of the slopes of the survival curves (SCC-25/CP to SCC-25) of the two lines was 43. At survivals of 1%, resistance to MEL and BCNU became evident in the SCC-25/CP line. At survivals of 0.1%, resistance to mitomycin C and, to a lesser degree, to Adriamycin and vincristine was evident. It is more difficult to produce resistance to alkylating agents, even with extended selection pressure, than to other antineoplastic drugs such as antimetabolites and natural products. We found no evidence of pleiotropic resistance in any alkylating agent-resistant cell line. Our results suggest that a judicious choice of alkylating agents given in sequential or concurrent combination may be a rational treatment strategy with potential applications in the clinic.

Alkylating Agents↗
PubMed1986

5-Fluorouracil treatment of a human colon adenocarcinoma implanted in the subrenal capsule site of athymic mice.

5-Fluorouracil was used in the treatment of a recently established. human adenocolon carcinoma implanted in the subrenal capsule site of athymic mice as part of a program to determine the relative effectiveness of antitumor agents in the treatment of human tumors grown as xenografts and in the clinic. 5-Fluorouracil treatments resulted in a dose-dependent inhibition of tumor growth under the two examined schedules (five daily doses and three doses every 4 days) when administered either i.v. or i.p. The various schedules and routes resulted in similar patterns of antitumor effects when the data were based on the endpoints of either final tumor weight, change in tumor weight, or relative tumor weight. Assessments of cell viability based on histological examination of tumored kidneys resulted in a downward displacement of the dose-response curves but did not alter their shape or the interpretation of the data. Although approximately 1-mm3 tumor fragments were implanted, variability of size was allowed. Tumor growth was not dependent on the initial size of the implant, as shown by a comparison between the initial individual or average tumor sizes and the final individual or average tumor sizes, respectively. The antitumor effects of the 5-fluorouracil could have been determined on the basis of final tumor weight alone. The inhibition of tumor growth was accompanied by weight loss in treated mice as compared with controls. At lower doses, however, the weight loss of the mice was not extensive, which indicated that the inhibition of tumor growth was, at least in part, attributable to some selective antitumor action of the 5-FUra. The greatest inhibition of tumor growth, however, was accompanied by the most extensive animal weight loss. This correlation raised the question of the degree to which the tumor growth inhibition observed was a consequence of nonspecific drug toxicity to the host. The current results stress the importance of detailed investigations into the nature of host-tumor parameters in order to assess the antitumor activity of candidate drugs in the treatment of human tumor xenografts.

Adenocarcinoma↗
PubMed1986

Role of murine tumor models in cancer treatment research.

Two major factors have contributed to a widely held disenchantment with murine tumor models for drug screening in cancer research: (a) the higher costs of these models in comparison to studies performed with tumor cells in vitro; and (b) the perception that these models have failed to demonstrate satisfactory correlation of chemosensitivity with analogous human tumor types; i.e., murine tumors generally have proved to be sensitive to many more agents than are found to be active in the clinic. The perceived failure of the murine models is discussed with particular reference to the difference in criteria used for evaluating drug sensitivity in murine tumor models versus clinical trials, and we conclude that the perception about murine models is not tenable in light of present information. The very important role of murine tumor models in optimizing dosage and administration schedules and, most importantly, in the development of a new drug to its most useful potential in combination chemotherapy is discussed. The value of this in vivo methodology is stressed.

Animals↗
PubMed1985

SQM1 antibody defines a surface membrane antigen in squamous carcinoma of the head and neck.

We produced murine monoclonal antibodies (MAbs) directed against the surface membrane of squamous-cell carcinoma of the head and neck (SCCHN). One antibody, SQM1, was determined by immunofluorescence and radioimmunoassay to be reactive with 13/13 SCCHN cell lines derived from different sites of the head and neck area. No binding reaction was observed with normal fibroblasts, red blood cells, nucleated bone-marrow cells or epithelial cells from normal oral mucosa. SQM1 reactivity was observed with primary cultures of normal epidermal and bronchial epithelial cells. Significant reactivity was found with 2/4 cell lines derived from small-cell carcinoma of the lung but little or no reactivity was found with other lung cancer cell lines. Various cell lines derived from other cancers including breast, colon, and ovarian carcinomas, melanoma, neuroblastoma and leukemia were generally unreactive. Seventeen out of 18 fresh frozen specimens of SCCHN were strongly reactive with SQM1 antibody. However, autopsy specimens from the heart, liver, kidney, spleen, colon, subcutaneous fat and skin connective tissue were unreactive. SQM1 antibody may be useful in biological and clinical studies of the head and neck region.

Antibodies, Monoclonal↗
PubMed1985

Cloning of the extra sex combs gene of Drosophila and its identification by P-element-mediated gene transfer.

A large region containing the extra sex combs (esc) gene of Drosophila has been cloned by microdissection from polytene chromosomes and chromosomal walking. Within this DNA, the segment comprising the esc gene has been narrowed down in several steps. First, a deletion of the esc gene, Df(2L)esc, defined a region of 380 kb. Then, a duplication carrying the esc gene, Dp(2;2)GYL, and a deletion not eliminating esc, Df(2L)prd, further reduced this region to 160 kb. Finally, because esc transcripts are expected to be present in follicles but absent in adult males, mapping of follicle and adult male transcripts limited the esc region to 10 kb. Rigorous proof that this DNA contained the esc gene was obtained by P-element-mediated transformation. We conclude that the 12 kb of DNA used for transformation include the esc gene as well as all flanking sequences required for its proper regulation in the female germ line.

Journal Article↗
PubMed1985

Influence of experimental diets on hepatic glutathione levels in rats with methylnitrosourea-induced mammary carcinoma.

Mammary tumor development induced by methylnitrosourea in female Sprague-Dawley rats had no significant effect on hepatic glutathione levels. If the diets of methylnitrosourea-treated animals were supplemented with vitamin A and E an increased hepatic glutathione level was observed initially. A high fat diet (21% per weight) supplemented with the two vitamins led to a decreased hepatic glutathione level 2 months after tumor induction. Advanced tumor development under any of the diets tested had no effect on hepatic glutathione.

Animals↗
PubMed1985

Influence of a prolonged treatment with disulfiram and D(-)penicillamine on nitrosodiethylamine-induced biological and biochemical effects in rats. I. Investigations on the drug metabolizing system.

The influence of a prolonged treatment with disulfiram (DSF) and D(-)penicillamine (PA) on biological and biochemical effects induced by nitrosodiethylamine (NDEA) was studied in rats. The combination of NDEA and DSF led to a massive and early development of esophageal tumors, which were fatal to the animals. No liver tumors were observed in this group, whereas PA in combination with NDEA led to an increased development of liver tumors compared with NDEA alone. In the last two groups, only incidental tumors of the esophagus were observed. Nasal cavity tumors also appeared earlier in the animals treated with DSF and NDEA than in animals treated with NDEA alone or with NDEA plus PA. At a biochemical level, DSF led to a significant inhibition of hepatic anilinehydroxylase and nitroso-dimethylaminedemethylase in contrast to PA, which had no influence on these enzymes. The reduced activities of these drug-metabolizing enzymes did not appear to be related to gross cytochrome P450 content. Highly significant increases in glutathione content and glutathione-S-transferase activity (GSH/GST) were induced by DSF but not by PA. Because N-nitrosodiethylamine requires enzymatic activation to form the ultimate carcinogen, it is suggested that the observed inhibition of nitrosamine-transforming enzymes in the liver during DSF treatment leads to an increased amount of intact nitrosamines in other organs, e.g., in the esophagus, where it could be transformed to the ultimate carcinogen. DSF treatment alone or in combination with NDEA leads to an accumulation of trace elements in the liver, whereas PA eliminated copper and cobalt. The possible influence of these elements on tumor development is discussed in part II of this study.

Animals↗