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Biomedical subjects

E Frei

Publications and source records attributed to E Frei.

At least 199 records · Page 11Linked to original sources
PubMed1988

Four patients with myelodysplastic syndrome with translocation (1;7)(p11;p11) including one patient with independent clones del(7)q22) [corrected] and t(1;7)(q21;q11)

A translocation involving the short arm of chromosome #1 and the short arm of chromosome #7, [t(1;7)(p11;p11)] was present in four patients with myelodysplastic syndrome (MDS). Two of these patients had prior lymphoproliferative disorders and developed MDS following prolonged therapy with alkylating agents. One of the patients with prior therapy history has two additional independent abnormal clones: one with a partial deletion of the long arm of #7 and the other with t(1;7)(q21;q11). A third patient had a family history of leukemia in both the father and a brother, both of whom developed acute nonlymphocytic leukemia following an MDS phase. The last patient was an elderly woman with no predisposing features.

Aged↗
PubMed1988

Influence of thiocompounds on the metabolism of N-nitrosodiethylamine.

Diethyldithiocarbaminate (DDTC), mercaptoethanesulfonate (MESNA) and ethylxanthate (PEX) were tested for their influence on N-nitrosodiethylamine (NDEA) metabolism. The exhalation rate of 14CO2 released from [14C]NDEA was decreased by PEX, but not by MESNA or DDTC. The sulfur compounds led to an increased excretion of unchanged NDEA in urine in the order PEX greater than DDTC much greater than MESNA. The activity of NDEA-deethylase in liver microsomal system was decreased only after DDTC or PEX treatment. Glutathione content and glutathione-S-transferase activity were not affected significantly by any of the tested compounds. NDEA-induced single-strand breaks in liver cell DNA were inhibited after PEX treatment.

Animals↗
PubMed1988

Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.

Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay (ELISA) test indicated plasma rH-TNF levels less than 0.2 U/mL. The recommended phase II dose of rH-TNF administered as a five-day continuous infusion is 2.4 X 10(5) U/m2/d.

Chemical and Drug Induced Liver Injury↗
PubMed1988

Chemotherapeutic strategies in the multidisciplinary treatment of head and neck cancer.

A role for chemotherapy in the multidisciplinary treatment of patients with advanced squamous cell carcinoma of the head and neck (SCCHN) is yet to be defined. Results of uncontrolled studies indicate high response rates to induction chemotherapy and an association between a response to chemotherapy and either local-regional control or survival. Unfortunately, results of randomized, controlled trials have not confirmed an overall survival advantage with such treatment. From 1979 to the present, the Dana-Farber Cancer Institute has registered more than 224 patients on two trials of induction and adjuvant chemotherapy for patients with stage III to IV SCCHN. Protocol 80-016 (1979 to 1983) evaluated two cycles of induction cisplatin, bleomycin, and methotrexate/leucovorin (PBM) before local regional treatment in 114 patients. Eighty-nine (78%) patients responded to PBM, with 30 (28%) patients achieving a complete response (CR). After surgery and/or radiotherapy (RT), 46 responders to induction PBM entered a trial of the randomly assigned additional adjuvant PBM. Protocol 83-084 (1983 to present) randomly assigned patients to receive up to four cycles of either induction PBM or cisplatin and infusion 5-fluorouracil before local treatment. Adjuvant chemotherapy was not used in the latter study. Updated results from both trials will be presented, with their implications for future phase II and III multidisciplinary studies. Optimal approaches to the treatment of patients with advanced SCCHN can include planned reductions in the extent of surgery or RT offered to selected patients with a good response to induction chemotherapy but may require adjuvant chemotherapy for patients at high risk for recurrent disease. Until the rate of CR to induction chemotherapy is reproducibly over 50%, documentation of an improved overall survival with multidisciplinary treatment may be difficult.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Collateral methotrexate resistance in cultured human head and neck carcinoma cells selected for resistance to cis-diamminedichloroplatinum(II).

A human head and neck squamous cell carcinoma line (SCC25) derived from a patient with no prior history of radiotherapy or chemotherapy was made resistant to cis-diamminedichloroplatinum(II) (CDDP) by continuous escalation of weekly 30-min pulses of the CDDP from 0 to 0.2 mM over 20 months and then cloned and pulsed weekly with 0.2 mM CDDP for another 20 months. This afforded a resistant subline, SCC25/CP[1], with an IC50 for CDDP 12-fold higher than that of the parental cells. The SCC25/CP[1] cells unexpectedly proved to be cross-resistant to methotrexate (MTX) (24-fold for 30-min treatment and 8-fold for continuous treatment). Resistance was associated with a modest (about 2-fold) increase in the dihydrofolate reductase (DHFR) content according to radioligand-binding assay, and in the rate of cell division. In addition there was a 4-fold decrease in the fraction of long-chain MTX polyglutamates MTX(G4-6) in the cell after 24 h exposure to either 0.2 or 2.0 microM MTX. When the SCC25/CP[1] cells were kept out of CDDP for 8-9 months and 12 months to give the sublines SCC25/CP[2] and SCC25/CP[3], respectively, MTX sensitivity to continuous exposure returned to normal. The SCC25/CP[3] cells still exhibited a slightly elevated DHFR level, but their generation time became shorter than that of the parental SCC25 line. In addition the SCC25/CP[3] cells had an initial uptake velocity (V0) for MTX that was 9-fold greater than the V0 of the SCC25 or SCC25/CP[1] cells, while its ability to form MTX(G4-6) was comparable to that of the SCC25 cells. When SCC25/CP[2] cells were rechallenged with weekly 0.2 mM CDDP pulses for 4-6 months, a MTX-resistant line, SCC25/CP[4], was produced. The SCC25/CP[4] cells retained a slightly elevated DHFR content and a high proliferation rate, but the V0 for MTX influx was intermediate between SCC25 and SCC25/CP[3] cells. The ability to form the longer-chain polyglutamates MTX(G4-6) was again impaired. Thus, MTX cross-resistance can develop in cultured head and neck carcinoma cells when CDDP is used as the selecting agent for primary resistance. MTX resistance is multifactorial, as it is when MTX itself is used as the selecting agent, and appears to involve various combinations of altered growth rate, DHFR content, MTX uptake, and ability to form noneffluxing long-chain MTX polyglutamate species. These results are potentially of clinical relevance, since CDDP and MTX are often used in combination with other drugs or with radiation to treat patients with squamous cell carcinoma of the head and neck.

Biological Transport↗
PubMed1987

Metabolism of methotrexate and gamma-tert-butyl methotrexate by human leukemic cells in culture and by hepatic aldehyde oxidase in vitro.

The cellular uptake and metabolism of methotrexate (MTX) and gamma-tert-butyl methotrexate (TBM) were compared in CEM human leukemic lymphoblasts and a highly MTX-resistant subline (CEM/MTX) in which MTX uptake is defective. The CEM/MTX cells were found previously to be as sensitive as the parent line to TBM. While MTX was polyglutamylated extensively in the CEM cells, giving abundant levels of non-effluxing conjugates, polyglutamylation in CEM/MTX cells was reduced severely, even after exposure to a high MTX concentration (100 microM) in the medium. This treatment provided free intracellular MTX in greater than 100-fold excess over the dihydrofolate reductase level. In contrast to MTX, the ester TBM was unmetabolized in either cell line. Uptake levels after incubation of CEM and CEM/MTX cells with 2 microM TBM for 24 hr were 17 and 15 pmol/mg protein respectively. Thus, TBM accumulated equally in both cells and was well retained despite the lack of polyglutamylation. These results, together with the previously observed affinity of the drug for dihydrofolate reductase, provide a plausible rationale for the comparable sensitivity of CEM and CEM/MTX cells to TBM. Experiments were also performed to determine the susceptibility of TBM to metabolic detoxification by hepatic aldehyde oxidase. Km values were 8-fold lower for TBM than for MTX in assays using an enzyme preparation from rabbit liver, and Vmax values were 8-fold higher. Neither MTX nor TBM was oxidized to its 7-hydroxy derivative in intact CEM or CEM/MTX cells. Because TBM is capable of overcoming at least one of the modalities of MTX resistance, defective polyglutamylation, and may be more efficiently detoxified than MTX by the action of hepatic aldehyde oxidase, it has the potential to be a useful agent for the treatment of MTX-resistant tumors.

Aldehyde Oxidase↗
PubMed1987

Response of drug-sensitive and -resistant L1210 leukemias to high-dose chemotherapy.

Alkylating agent-sensitive and -resistant L1210 leukemia cell lines were used to determine the tumor response to dose levels of drugs that exceeded conventional doses up to a factor of 10. Since those dose levels were lethal to the host mice, tumor response was based on the results of in vivo bioassays of spleen and/or tumor from drug-treated and control mice. When mice bearing about 10(8) drug-sensitive leukemic cells were treated with a single, conventional (approximately 10% lethal) dose of cis-diamminedichloroplatinum, L-phenylalanine mustard (melphalan), or 1,3-bis(2-chloroethyl)-1-nitrosourea, 10(1) to 10(4) tumor cells were recovered by bioassay. Treatment at doses that were 2 to 8 times the 10% lethal dose of either of those drugs resulted in no recoverable cells and survival of all bioassay recipient mice. Mice bearing advanced L1210 leukemia resistant to cis-diamminedichloroplatinum (L1210/DDPt), 1,3-bis-(2-chloroethyl)-1-nitrosourea (L1210/BCNU), cyclophosphamide (L1210/CPA), or melphalan(L1210/L-PAM) also were treated with a 10% lethal dose and greater doses of the drug to which the tumor line was resistant. Bioassay results indicated a direct correlation between dose intensity and tumor cell kill, the response being linear. Similarly, when mice with L1210/BCNU were treated with high doses of N-(2-chloroethyl)-N''-(2,6-dioxo-3-piperidinyl)-N-nitrosourea or 1,1',1''-phosphinothioylidynetrisaziridine (thioTEPA) and when mice with L1210/DDPt were treated with cyclophosphamide, an increasing, linear cell kill resulted throughout the high-dose range. Overall, these results indicate that resistance to these alkylating agents can be overcome by dose intensification and that the tumor response is linear in relation to increasing dose level.

Alkylating Agents↗
PubMed1987

Characterization of a human squamous carcinoma cell line resistant to cis-diamminedichloroplatinum(II).

We have developed a human head and neck squamous cell carcinoma cell line (SCC-25/CP) which is relatively stably resistant to cis-diamminedichloroplatinum(II) (CDDP) after repeated exposure to escalating doses of the drug. The studies reported elucidate the mechanism(s) by which the SCC-25/CP cell line is resistant to CDDP. The SCC-25/CP cell line is approximately 30-fold resistant to CDDP, approximately 10-fold resistant to carboplatin, and about 9-fold resistant to iproplatin. Using [195mPt]CDDP, we examined the levels of platinum in whole cells and cellular fractions of both the SCC-25 and SCC-25/CP cells after 1 h exposure to 100 microM drug. The SCC-25 cells took up 30 pmol of platinum/10(6) cells in 1 h; 64% of the drug was in the nucleus and 21% in the cytosol. The SCC-25/CP cells took up 7 pmol of platinum/10(6) cells; of this, 41% was in the nucleus and 33% in the cytosol. The SCC-25 cell nuclei contained 331 pmol of platinum/mg protein and the cytosol 21 pmol of platinum/mg protein, whereas the SCC-25/CP cell nuclei contained 47 pmol of platinum/mg protein and the cytosol 8.1 pmol/mg protein. The release of drug from both cell lines followed a very similar course and was most rapid over the first 6 h. There was no difference in the non-protein sulfhydryl content of the cell lines. The protein sulfhydryl content, as measured by Ellman's procedure, indicated that the SCC-25/CP cell line has approximately a 2-fold increase in protein sulfhydryl content compared to the SCC-25 cell line. The SCC-25/CP cell line is about 2-fold resistant to cadmium chloride at 50% cell kill and about 2.5-fold resistant at 1 log kill compared to the SCC-25 cell line. Glutathione transferase activity in crude cytoplasmic extracts was measured and found to be approximately 2- to 3-fold higher in the CDDP resistant cells. The isoelectric point of the glutathione transferase isozyme was 4.8 in both the sensitive and resistant cell lines, suggesting induction of the predominant isozyme present in the parent cell line. By alkaline elution there was greater cross-link formation by CDDP in the SCC-25 cell line than in the SCC-25/CP cell line at the same drug concentrations. In conclusion, the mechanism of resistance of the SCC-25/CP cell line to CDDP is multifactorial, involving plasma membrane changes, increased cytosolic binding, and decreased DNA cross-linking.

Biological Transport↗
PubMed1987

Clinical studies with tumour necrosis factor.

The mechanism of tumour necrosis factor (TNF) cytotoxicity remains unknown. The in vivo antitumour effects of TNF may be related to direct cytotoxicity, immunomodulatory effects or endothelial effects on tumour vasculature. Phase I and early Phase II clinical trials of human recombinant TNF are under way in Japan, the USA, the UK and Germany. The maximum Phase II dose for TNF has not been established. The clinical toxicity of TNF is generally similar to that of other biological agents. Systemic toxicity, including fever, chills, anorexia and nausea, has been seen in most patients treated with TNF and has not been clearly related to dose. Other toxicities have included liver function abnormalities, hypotension, transient neurological changes and haematological abnormalities. Few clinical responses have been reported but organized Phase II testing remains to be completed. Combination trials with interferons have recently been initiated. Phase II efficacy studies of TNF as a single agent and in combination are needed for an assessment of the value of this agent in cancer therapy.

Chemical and Drug Induced Liver Injury↗
PubMed1987

Dihydrofolate reductase-activity in brain tissue. Effect of X-irradiation.

The mechanism responsible for the toxic late effects of cranial irradiation, followed by the administration of systemic methotrexate (MTX) on brain tissue, is still under discussion. We studied the influence of X-irradiation on dihydrofolate reductase (E.C. 1.5.1.3) activity (DHFR), the enzyme inhibited by MTX. New Zealand white rabbits, 6-9 weeks old, underwent 24 Gy fractionated or 20 Gy single-dose brain irradiation using a 60Co source. Before, immediately following, and 1, 2, 4, 12 weeks after irradiation, DHFR was measured in brain and liver tissue by a photometric assay. DHFR in brain tissue was 11.9 +/- 2.9 mU/g wet weight (ww) X h and in liver tissue 121.8 +/- 24.2 mU/g ww X h. Fractionated brain irradiation with 2 Gy per day produced no significant changes in brain DHFR. Single-dose cranial irradiation significantly decreased brain DFHR (7.3 +/- 0.6 mU/g ww X h). Suppression of the developmental increase of DHFR by X-irradiation in young rabbits could be excluded by determining the unchanged brain-to-liver ratios of DHFR in the animals with fractionated brain irradiation.

Animals↗
PubMed1987

Weekly high-dose methotrexate and doxorubicin for osteosarcoma: the Dana-Farber Cancer Institute/the Children's Hospital--study III.

Weekly high-dose methotrexate with leucovorin rescue and vincristine (HDMTX) and doxorubicin was administered as adjuvant postoperative therapy to 46 patients with a diagnosis of conventional high-grade nonmetastatic osteosarcoma of an extremity between July 1976 and December 1981. The primary lesions were managed by wide or radical amputation (26 patients) or by limb-sparing resection in 20 selected patients. The margins of the resections were retrospectively classified as marginal in three, wide in 16, and radical in one. The 5-year relapse-free survival (RFS) for all patients is 59% (95% confidence interval [CI], 43%, 74%) and overall survival is 78% (95% CI, 65%, 91%). The RFS for patients initially having a limb resection procedure is 55% (95% CI, 32%, 77%) compared with 62% (95% CI, 43%, 81%) for those initially having amputations (P = .52). Using multivariate analysis, the only significant prognostic variables that predicted RFS of greater than or equal to 3 years, were the presence of moderate to marked lymphocytic infiltration of the primary tumor (P less than .002), primary site outside of the proximal humerus (P less than .005), and the absence of a predominance of osteoblastic pattern in the primary tumor (P less than .03).

Actuarial Analysis↗
PubMed1987

Induction chemotherapy as initial treatment for advanced head and neck cancer: a model for the multidisciplinary treatment of solid tumors.

The role of chemotherapy in the management of patients with SCCHN has not been adequately defined. For patients with recurrent or metastatic disease, several single agents can induce significant tumor regression in 20% to 40% of cases and provide palliation for the individual with a symptomatic or life-threatening lesion. However, complete or long-term control of tumor with chemotherapy alone remains poor. In addition, current regimens of combination chemotherapy have not proved superior to single agents in this setting. Thus, the routine use of combination chemotherapy for patients with metastatic or recurrent SCCHN cannot be justified outside an investigational study. New single agents of promise must be sought and more active combinations of chemotherapy devised for the treatment of patients with metastatic or recurrent SCCHN. Strategies for drug development include the investigation of cisplatin analogues, such as iproplatin and carboplatin, the exploitation of potentially synergistic drug schedules, and the administration of chemotherapy by continuous infusion. That the use of continuous-infusion drug delivery can enhance antitumor activity and limit toxicity for patients with recurrent or metastatic SCCHN was convincingly demonstrated by Kish and co-workers132 in a randomized trial of cisplatin with either bolus or continous-infusion 5-fluourouracil. The antitumor activity of combination chemotherapy may also be increased by the use of mid-cycle nonmyelosuppressive agents, such as methotrexate with leucovorin rescue, or the administration of alternating cycles of non-cross-resistant regimens of combination chemotherapy. The optimal use of chemotherapy in the multidisciplinary treatment of patients with previously untreated SCCHN must also be clarified. Uncontrolled studies of induction chemotherapy report increasingly positive results. Several regimens of induction combination chemotherapy are now associated with significant tumor regression in 70% to 90% of patients, and complete clinical regression of tumor in 20% to 50%. Of patients with a complete clinical response to induction chemotherapy, a complete pathologic response has been documented in 30% to 70% of patients who undergo surgical resection after chemotherapy. It is now evident that patients achieving a complete response to induction chemotherapy have a high probability of local-regional control of tumor and cure. Conversely, patients not responding to induction chemotherapy fare poorly regardless of subsequent local treatment, and it may be appropriate to defer excessively morbid surgical procedures in this patient populus.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗
PubMed1987

Investigation into the pharmacodynamics of the carcinogen N-nitrodimethylamine.

N-Nitrodimethylamine (NTDMA) was found to be a carcinogen of the nasal mucosa leading to aesthesioneuroepitheliomas in BDVI rats. N-Nitromethylamine (NTMA), a product of the oxidative metabolism of NTDMA, was also carcinogenic, leading to neurogenic tumours of the lumbar region of the spine. The 100,000 X g supernatant of both liver and nasal mucosa contains an enzyme capable of reducing NTDMA to N-nitrosodimethylamine (NDMA). In the microsomal fraction of both organs, NTDMA is oxidized to formaldehyde. The fractions from nasal mucosa have a higher capacity than the corresponding liver fractions to both oxidize and reduce NTDMA. NDMA was detected in blood and urine from rats treated with NTDMA. The elimination of NTDMA from blood occurs biphasically, with an initial half-life of 3.5 min.

Anaerobiosis↗