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Biomedical subjects

E Frei

Publications and source records attributed to E Frei.

At least 19 recordsLinked to original sources
PubMed1992

Continuous-infusion cisplatin, 5-fluorouracil, and bolus methotrexate in the treatment of advanced non-small cell lung cancer.

BACKGROUND: Cisplatin and 5-fluorouracil have noted synergy in preclinical systems. The authors combined methotrexate with infusional cisplatin and 5-fluorouracil in an attempt to produce a regimen with improved activity in advanced NSCLC: METHODS: Twenty-six ambulatory patients with previously untreated non-small cell lung cancer were treated with continuous-infusion cisplatin (25 mg/m2/day for 5 days), 5-fluorouracil (800 mg/m2/day for 5 days), and intermediate-dose methotrexate (200 mg/m2 on days 15, 22), followed by leucovorin rescue (PFM regimen). RESULTS: Patients received a median of four cycles of therapy. Two patients had a complete response, and 10 had a partial response (overall response rate, 46.2% or 12 of 26). The median time to treatment failure was 22.5 weeks; the median survival was 55 weeks from the start of chemotherapy. There were no toxic deaths attributed to chemotherapy. Thrombocytopenia was the only Grade 4 toxicity (27%). Grade 1/4 and 2/4 peripheral neuropathy occurred in 17 of 26 patients (66%) and was associated with a cumulative cisplatin dose of more than 300 mg/m2. CONCLUSIONS: PFM (using continuous-infusion cisplatin) produced a high response rate but resulted in an high incidence of low-grade peripheral neuropathy.

Adult↗
PubMed1992

Hormonal perturbations in patients with testicular cancer treated with cisplatin.

Patients with testicular cancer treated with cisplatin can undergo feminization that is understood poorly. Rat model studies recently showed that cisplatin can feminize in part the profile of hepatic steroid-metabolizing enzymes and circulating hormone levels. This study was undertaken to determine whether cisplatin similarly might contribute to the perturbations in gonadotropin or steroid hormone levels that can occur in patients undergoing cisplatin-based treatment for testicular cancer. Analysis of serum free testosterone, total testosterone, and androstenedione levels revealed that these hormones were not altered significantly in patients during a 38-week period of cisplatin-based treatment and follow-up. Estradiol levels were elevated before chemotherapy and were reduced to normal levels during treatment. This reduction was attributed to the cytotoxic effect of chemotherapy on the tumors and the resultant reduction in serum chorionic gonadotropin levels. Serum dihydrotestosterone (DHT) levels were normal before chemotherapy but progressively became elevated during treatment with cisplatin in five of ten patients examined. The rise in DHT may relate to the previously described increase in hepatic androgen 5 alpha-reductase activity in cisplatin-treated rats. Levels of the gonadotropins, luteinizing hormone, and follicle-stimulating hormone (FSH) were normal before cisplatin-based treatment was administered; however, FSH was elevated selectively during chemotherapy. This selective induction of FSH may reflect an effect of cisplatin on the hypothalamic secretion of gonadotropin-releasing hormone. Taken together, these findings suggest that cisplatin contributes to the perturbation of steroid and peptide hormone levels in patients with testicular cancer and perhaps in others undergoing cisplatin-based chemotherapy.

Adult↗
PubMed1992

Peroxidase oxidizes N-nitrosomethylaniline to ultimate carcinogens(s) binding to DNA and transfer RNA in vitro.

Carcinogenic N-nitrosomethylaniline is oxidized in vitro by horseradish peroxidase in the presence of H2O2 to ultimate carcinogens, which bind to DNA and transfer RNA (tRNA). tRNA is more accessible for modification by the activated carcinogen studied. The modification of nucleic acid by N-nitrosomethylaniline metabolite(s) formed by peroxidase is inhibited by some compounds of physiological importance (ascorbate, glutathine) and by radical trapping agents (nitrosobenzene, methyl viologen). 32P-postlabeling assay of DNA and tRNA modified by N-nitrosomethylaniline activated by peroxidase shows covalent adduct formation with nucleic acids. The role of peroxidases in the activation of N-nitrosamines leading to organ and/or cell specificity of these carcinogens is discussed.

Autoradiography↗
PubMed1992

Minocycline in combination with chemotherapy or radiation therapy in vitro and in vivo.

In the present study the potential of minocycline, a semisynthetic tetracycline that inhibits collagenase activity in vivo, as an adjuvant to standard anticancer therapies was explored in vitro and in vivo. In EMT-6 cells, minocycline proved to be only minimally cytotoxic, producing a 50% cell kill at concentrations of 132 and 220 microM in normally oxygenated and hypoxic cells, respectively, after 24 h exposure to the drug. In vitro, there appeared to be no interaction between minocycline and cisplatin (CDDP), melphalan, 4-hydroperoxycyclophosphamide, or radiation. In tumor-cell survival studies using the FSaIIC murine fibrosarcoma, short-term treatment with minocycline (5 x 5 mg/kg given over 24 h) was only minimally cytotoxic and did not alter the tumor response to a range of radiation doses. However, when minocycline (5 x 5 mg/kg given over 24 h) was added to treatment with cyclophosphamide, there was a 4-fold increase in FSaIIC tumor-cell killing across the dose range of cyclophosphamide doses tested, whereas the killing of bone marrow granulocyte macrophage colony-forming units (CFU-GM) remained unchanged. The Lewis lung carcinoma was used to assess the response of both the primary tumor and metastatic lung disease to treatment with minocycline (14 x 5 mg/kg) given alone or in combination with several cytotoxic anticancer drugs or with radiation delivered locally to the primary tumor. Of the various therapies tested, minocycline proved to be especially effective as an addition to treatment with cyclophosphamide both in increasing the response of the primary tumor and in reducing the number of lung metastases. The tumor growth delay produced by melphalan, radiation, Adriamycin, and bleomycin was also increased by the addition of minocycline to these therapies. These results indicate that minocycline given in clinically achievable doses may be an effective addition to some standard therapeutic regimens and that the mechanism of modulation by minocycline is likely to involve an effect of the drug on the host and not its direct interaction with other therapeutic modalities at the level of the tumor cell.

Animals↗
PubMed1992

1-C-glucuronidation of N-nitrosodiethylamine and N-nitrosomethyl-n-pentylamine in vivo and in primary hepatocytes from rats pretreated with inducers.

The organ specificity of the carcinogenic action of nitrosamines is partly explained by organ specific activation. The specificity might also be determined by conjugation of reactive intermediates in e.g. the liver. 14C-Labeled N-nitrosodiethylamine (NDEA) a liver carcinogen and N-nitrosomethyl-n-pentylamine (NMPentA) which induces esophageal and nasal tumors were administered to rats or incubated with primary cells. Urine and cell extracts were separated by HPLC after addition of synthetic marker glucuronides and these were quantified by liquid scintillation counting. In urine of rats treated with NDEA 0.03% of administered nitrosamine was recovered as the O-glucuronide derived from N-nitroso-1-hydroxyethylethylamine. In rats treated with NMPentA 2.86% was metabolized to the glucuronide at the methyl group. In hepatocytes of untreated rats 0.03% of the added NDEA was conjugated to the glucuronide, phenobarbital pretreatment induced this conjugation reaction 5-fold. Hepatocytes from untreated rats metabolized 1.2% of NMPentA to the primary glucuronide; after phenobarbital pretreatment this value increased to 1.6%. In hepatocytes from 3-methylcholanthrene-pretreated rats, 0.04% of NMPentA was metabolized to the glucuronide derived from N-nitroso-1-hydroxy-n-pentyl-methylamine, while 0.85% was derived from N-nitroso-hydroxymethyl-n-pentylamine. In hepatocytes from Aroclor-pretreated rats, 0.09% were pentyl conjugates and 1.1% methyl conjugates. The induction pattern and organ specificity of glucuronidation indicate that all three 1-hydroxy nitrosamines are conjugated by group II phenobarbital inducible UDP-glucuronosyltransferase activity. The lipophilicity of a nitrosamine seems to determine the extent of glucuronidation in hepatocytes and in vivo. No glucuronides derived from either NDEA or NMPentA were detectable in incubations with kidney cells, nor was the glucuronide of NDEA found in incubations with whole bladders.

Animals↗
PubMed1992

32P-postlabeling analysis of adducts formed from 1-phenylazo-2-hydroxynaphthalene (Sudan I, Solvent Yellow 14) with DNA and homopolydeoxyribonucleotides.

A 32P-postlabeling assay was employed for detection and quantitation of DNA adducts formed with carcinogenic 1-phenylazo-2-hydroxynaphthalene (Sudan I, Solvent Yellow 14) activated by a peroxidase system. Enrichment of adducts by digestion with nuclease P1 or by extraction into n-butanol prior to 32P-labeling was used. Both enrichment procedures exhibited comparable results for recovery of individual DNA adduct spots. Co-chromatographic analyses of adduct spots obtained by reaction with DNA and homopolydeoxy-ribonucleotides showed that four out of the eight major Sudan I-DNA adducts were formed by reaction of activated Sudan I with deoxyadenosine or deoxyguanosine in DNA. The accuracy of quantitation of adducts by 32P-postlabeling procedure is discussed.

Autoradiography↗
PubMed1992

Formation and 32P-postlabeling of DNA and tRNA adducts derived from peroxidative activation of carcinogenic azo dye N,N-dimethyl-4-aminoazobenzene.

Peroxidase in the presence of hydrogen peroxide catalyzes in vitro the activation of carcinogenic N,N-dimethyl-4-aminoazobenzene (DAB) to DNA-, tRNA- and homopolydeoxyribonucleotide-bound products. tRNA is the most susceptible to modification by the activated DAB. Binding of DAB products to macromolecules is inhibited by methyl viologen, nitrosobenzene, ascorbate, glutathione, NADH and MgCl2. The mechanism of these inhibitions was studied. The nuclease P1 version of the 32P-postlabeling assay was employed for detection and quantitation of some major DNA or tRNA adducts formed with DAB activated by a peroxidase system. tRNA modified by activated DAB shows a significantly increased acceptance for L-methionine.

Animals↗
PubMed1992

Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response.

BACKGROUND: Cyclophosphamide, which forms the nucleus for virtually all preparative regimens for autologous bone marrow transplantation (ABMT), is an alkylating agent of which cytotoxicity is not directly caused by the parent compound but by its biologically active metabolites. Its nonmyelosuppressive toxicity in the ABMT setting is cardiomyopathy. We attempted to determine any correlation between plasma levels of total cyclophosphamide and the subsequent development of cardiac dysfunction. PATIENTS AND METHODS: Analyses of plasma levels and the derivation of plasma concentration-time curves (area under the curve [AUC]) were performed in 19 women with metastatic breast carcinoma, who received a continuous 96-hour infusion of cyclophosphamide, thiotepa, and carboplatin (CTCb) with ABMT. The assay for total cyclophosphamide measures the inactive parent compound; reliable assays of the active metabolites of cyclophosphamide are not yet available. RESULTS: Six of 19 women developed moderate, but transient, congestive heart failure (CHF) as assessed by clinical and radiologic criteria. These patients had a significantly lower AUC of total cyclophosphamide (median, 2,888 mumol/L/h) than patients who did not develop CHF (median, 6,121 mumol/L/h) (P less than .002). Median duration of tumor response in these patients was also more durable; at least 22 months in patients with lower AUCs versus a median of 5.25 months in those with higher AUCs (P = .008). CONCLUSION: These pharmacokinetic data support the premise that enhancement of cyclophosphamide activation may lead to both greater tumor cytotoxicity and increased but reversible end-organ toxicity. Early analysis of pharmacokinetic data may allow modulation of cyclophosphamide administration in an attempt to enhance therapeutic efficacy.

Adult↗
PubMed1992

Comparison of cytochrome P-450- and peroxidase-mediated activations of carcinogenic azo dyes and N-nitrosamines.

Carcinogenic azo dyes (dimethylaminoazobenzene, Sudan I) and N-nitrosamines (N-nitrosomethylaniline, N-nitrosomethylbenzylamine) are oxidized by cytochrome P-450 isoenzymes and peroxidase yielding metabolites which in vitro bind to DNA and transfer RNA (tRNA). The parallelism and differences in oxidative reactions are described. Peroxidase is more effective than P-450 in activating reactions of some carcinogens studied. The presence of either of these enzymes is supposed to be responsible for the organ and/or cell type specific effects of the carcinogens studied.

Animals↗
PubMed1992

[Appendectomy: open or laparoscopic?].

Surgeons interest in laparoscopic surgery has grown considerably in the last years, mostly due to the explosive spread of laparoscopic cholecystectomy. Laparoscopic appendectomy is from a historical point of view the older procedure, since it was already performed 1982 by Semm. His technique was modified 1987 by Götz, who is also responsible for popularizing it in general surgery. Between April 1989 and April 1991 we have performed 107 laparoscopic appendectomies. 82 were completed successfully by laparoscopy, in 25 instances we had to convert to an open procedure, mostly as a result of the lack of proficiency in the learning period. There were 8 septic complication (9.7%), a rather high rate, which probably will be reduced with the increasing operative expertise. There were no deaths in this series. Further experience is demanded in order to establish laparoscopic appendectomy as the alternative to the conventional procedure.

Abdomen, Acute↗
PubMed1992

Pulmonary toxicity associated with high dose chemotherapy in the treatment of solid tumors with autologous marrow transplant: an analysis of four chemotherapy regimens.

We retrospectively reviewed the pulmonary toxicity of six high dose chemotherapy protocols using four chemotherapy regimens in the treatment of solid tumors. All protocols used either high dose cyclophosphamide or ifosfamide in combination with one to three additional chemotherapeutic agents. In each protocol autologous bone marrow was reinfused post chemotherapy to shorten the period of severe myelosuppression. Of 178 patients there were 20 cases of fatal or life-threatening pulmonary toxicity including nine cases of pneumonia, nine cases of interstitial pneumonitis and two cases of pulmonary hemorrhage. Pulmonary function tests revealed modest changes in FEV1 and DLCO in the majority of patients, although 24 patients had more dramatic changes in DLCO suggesting interstitial damage. Significant decrements in FEV1 were seen in the BCNU containing regimen. Statistically significant or nearly significant decreases in DLCO were seen after all cyclophosphamide containing regimens. A regimen containing ifosfamide, carboplatin, and etoposide had minimal associated pulmonary toxicity.

Adolescent↗
PubMed1991

Etoposide with lonidamine or pentoxifylline as modulators of alkylating agent activity in vivo.

In an effort to improve the additive anti-tumor efficacy of commonly used alkylating agents, the topoisomerase-II inhibitor etoposide was used in combination with either the mitochondrial poison and energy-depleting agent lonidamine or the hemorheologic agent and tumor-blood-flow-increasing agent pentoxifylline. In the FSaIIC murine fibrosarcoma system, these modulators were evaluated for modulation of whole-tumor cell killing vs. bone-marrow CFU-GM toxicity with the alkylating drugs CDDP, CTX, L-PAM or BCNU. Etoposide alone was essentially additive with the alkylating drugs for both tumor-cell and bone-marrow killing, except for BCNU, where a substantial increase in tumor-cell killing occurred (0.5 to 2.0 logs over the dose range of BCNU tested) without a significant increase in bone-marrow toxicity. Etoposide plus lonidamine was significantly more active than etoposide alone only with CTX and BCNU in tumor-cell vs. bone-marrow killing. Etoposide plus pentoxifylline was also most active with these two alkylating agents, where increases in tumor-cell killing of 0.5 to 1.0 log were observed. Hoechst-33342-defined tumor-cell sub-population studies revealed that etoposide significantly improved the killing of dim (putative hypoxic) cells by CDDP, but neither lonidamine nor pentoxifylline significantly improved killing of bright or dim cells together. With CTX, etoposide plus lonidamine or pentoxifylline substantially improved killing of dim cells over etoposide alone (each by about 0.8 logs). These data indicate that a therapeutic advantage may be achievable by combining etoposide with lonidamine or pentoxifylline for use with alkylating drugs.

Alkylating Agents↗
PubMed1991

Effect of dietary calorie and fat restriction on mammary tumor growth and hepatic as well as tumor glutathione in rats.

Effect of dietary calorie restriction and fat reduction on growth of established mammary carcinoma in rats and on glutathione levels in liver and tumor tissue was investigated. Reduced (GSH) and oxidized (GSSG) glutathione were determined enzymatically. Female Sprague-Dawley rats were injected with 25 mg/kg methylnitrosourea (MNU) on day 50 of life for tumor induction, and subsequently fed a diet containing 50 kcal/day with 45% (energy %) fat. When tumors reached approximately 1 cm3, the diet was changed for 10 +/- 2 weeks. Four dietary groups were formed: two high calorie groups (50 kcal/day) with 45% or 25% fat and two calorie restricted groups (35 kcal/day) with 45% or 25% fat, respectively. Tumor growth was significantly inhibited by the 30% calorie restriction, and the inhibition was most effective in the calorie restricted group with low fat level. However, reduction of fat, alone, had no significant inhibitory effect. GSSG levels in both liver and tumor showed no differences among the groups. Hepatic GSH levels tended to be lower in the calorie-restricted groups, and showed no difference between isocaloric groups with different fat levels. In contrast, GSH in tumor tissue tended to be lower in the low fat groups, independently of calorie levels.

Animals↗
PubMed1991

Modulation of alkylating agents by etanidazole and Fluosol-DA/carbogen in the FSaIIC fibrosarcoma and EMT6 mammary carcinoma.

Tumor cell survival assay in the FSaIIC murine fibrosarcoma demonstrated that when the modulator Fluosol-DA (0.3 ml; 12 ml/kg i.v.) was administered just prior to an alkylating agent plus carbogen breathing for 6 h or the modulator etanidazole (1 g/kg i.p.) was administered just prior to an alkylating agent, the combination treatment produced significantly more tumor cell killing across the dosage range of each alkylating agent tested compared with the alkylating agent alone. Each alkylating agent produced a dose-dependent log-linear tumor cell survival curve. There was an increase in tumor cell killing of 5-10-fold when either Fluosol-DA/carbogen or etanidazole was added to treatment with the alkylating agent. For cis-diamminedichloroplatinum(II) (CDDP) and N,N',N''-triethylenethiophosphoramide, the modulators used in combination increased tumor cell killing by only 2-3-fold over that obtained with a single modulator, but for the other alkylating agents, tumor cell killing was increased by 10-50-fold when the combination of modulators was used. Bone marrow granulocyte-macrophage colony-forming unit survival assays showed that the combination of modulators with the alkylating agents resulted in only small increases in bone marrow toxicity of the alkylating agents except for N,N',N''-triethylenethiophosphoramide and L-phenylalanine mustard (L-PAM), for which the toxicity to the bone marrow granulocyte-macrophage colony-forming unit was increased by 5-10-fold compared with the alkylating agents alone. The Hoechst 33342 dye diffusion defined tumor cell subpopulation assay, also in the FSaIIC tumor, demonstrated that the combination of modulators increased the toxicity of CDDP, cyclophosphamide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea by 9-55-fold compared with the alkylating agent alone in both the bright (euxoic-enriched) and dim (hypoxic-enriched) cells. For each alkylating agent except 1,3-bis(2-chloroethyl)-1-nitrosourea, the increase in tumor cell killing was greater in the dim cells than in the bright cells. Finally, tumor growth delay studies in both the FSaIIC tumor and the EMT-6 murine mammary adenocarcinoma confirmed that the combination of modulators significantly increased the tumor growth delay caused by CDDP, carboplatin, cyclophosphamide, N,N'N"-triethylenethiophosphoramide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea. The greatest increases (4-5-fold) were observed for carboplatin and L-PAM in the FSaIIC tumor and CDDP and cyclophosphamide in the EMT-6 tumor. These results suggest that Fluosol-DA/carbogen together with etanidazole may be an effective modulator combination of alkylating agents in the clinic.

Alkylating Agents↗
PubMed1991

Lonidamine as a modulator of alkylating agent activity in vitro and in vivo.

We are searching for relatively nontoxic compounds that can positively modulate the efficacy of antitumor alkylating agents. Lonidamine inhibits cellular energy metabolism and could potentially increase damage by alkylating agents if cellular defenses are energy requiring. Exposure of cells to lonidamine (500 microM) for 2 h under hypoxic conditions followed by 1-h exposures to lonidamine plus alkylating agents under normally oxygenated conditions in vitro significantly increased the cell kill achieved by cis-diamminedichloroplatinum(II) (CDDP) approximately 5-fold and by D-tetraplatin approximately 10-fold at 90% inhibitory concentration in MCF-7/CDDP (CDDP-resistant) cells. Carboplatin cytotoxicity, however, was little changed. In the MCF-7 parent cell line, treatment with lonidamine increased CDDP cytotoxicity by approximately 10-fold, D-tetraplatin by approximately 10-fold, and carboplatin by approximately 8-fold at the 90% inhibitory concentration. For L-phenylalanine mustard (melphalan), N,N',N"-triethylenethiophosphoramide (thiotepa), and N,N'-bis(2-chloroethyl)-N-nitrosourea, little resistance was evident in the MCF-7/CDDP lines compared with the parent line. Treatment with lonidamine increased the cytotoxicity of each drug by 1.5- to 3-fold in both cell lines. When exposure to lonidamine was extended to 24 h before and 12 h after drug exposure in MCF-7 normally oxygenated cultures, CDDP (250 microM) cytotoxicity was increased by approximately 100-fold, but melphalan cytotoxicity was increased only 2- to 3-fold over the concentration range tested. In the FSaIIC murine fibrosarcoma tumor system, five i.p. injections of 50 mg/kg of lonidamine over 36 h increased the tumor cell kill by CDDP and carboplatin approximately 2- to 3-fold over the dose range tested when the platinum complexes were given i.p. immediately after the third lonidamine injection. When cyclophosphamide and thiotepa were given in the same schedule, 10-fold increases in tumor cell killing were evident on tumor excision assay over the dosage ranges. The increase in bone marrow toxicity caused by lonidamine in addition to the alkylating agents was less than for tumor cells. Finally, in the EMT6 murine mammary carcinoma, use of lonidamine at 500 mg/kg twice daily along with CDDP, carboplatin, thiotepa, and cyclophosphamide significantly increased tumor growth delays by approximately 1.6- to 3.0-fold. The results suggest that lonidamine can positively modulate antitumor alkylating agent cytotoxicity and may be a clinically useful adjunctive therapy with these drugs.

Animals↗