Search PubMed⌕ Search

Biomedical subjects

E Frei

Publications and source records attributed to E Frei.

At least 163 records · Page 9Linked to original sources
PubMed1990

Detoxifying potential of thioproline against N-nitroso compounds, N-nitrosodimethylamine and N-nitrosocimetidine.

Thioproline (TPRO), an effective nitrite trapping agent in vivo, was examined for its detoxifying ability in rats against N-nitrosodimethylamine (NDMA) and N-nitrosocimetidine (NCIM). When NDMA (37-101.5 mg/kg) was administered with TPRO (532 mg/kg), no influence of TPRO on NDMA-induced lethality and histological results in liver were observed. NDMA oxygenase activity measured by formaldehyde formation was not affected either. Denitrosation is a route of detoxication of N-nitroso compounds. When NCIM (100 mg/kg), a direct acting mutagen but not carcinogen, was given by gavage with TPRO, urinary excretion of N-nitrosothioproline (NTPRO) in rats apparently increased compared with TPRO alone. This result shows that TPRO is a trapping agent in vivo for nitrosating (NO) species originating from N-nitroso compounds, e.g., NCIM, which are denitrosated non-enzymatically in stomach acidic conditions. Transnitrosation from NDMA to TPRO, where enzymatic denitrosation is required, did not occur in measurable amount after oral administration of NDMA and TPRO.

Animals↗
PubMed1990

Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo.

EMT-6 murine mammary tumors were made resistant to cis-diamminedichloroplatinum (II) (CDDP), carboplatin, cyclophosphamide (CTX), or thiotepa in vivo by treatment of tumor-bearing animals with the drug during a 6-month period. In spite of high levels of in vivo resistance, no significant resistance was observed when the cells from these tumors were exposed to the drugs in vitro. The pharmacokinetics of CDDP and CTX were altered in animals bearing the respective resistant tumors. The resistance of all tumor lines except for the EMT-6/thiotepa decreased during 3 to 6 months in vivo passage in the absence of drugs. These results indicate that very high levels of resistance to anticancer drugs can develop through mechanisms that are expressed only in vivo.

Alkylating Agents↗
PubMed1990

N-nitrosamino phosphates are unlikely transport forms for activated nitrosamines.

Some of the target organs for nitrosamine carcinogenicity have a low activating capacity but many carcinogenic nitrosamines can be activated in the liver. Conjugates, such as phosphates, are chemically accessible reaction products of 1-OH-nitrosamines, and are either potential detoxication products or potential transport forms for activated nitrosamines. 14C-labeled 1-(N-ethyl-N-nitrosamino)ethyl phosphate was tested for its ability to enter primary rat hepatocytes but no uptake was detectable. No uptake was observable into fibroblasts and human leukocytes. N-Nitrosomethylbenzylamine is efficiently 1-C-hydroxylated by hepatocytes but the corresponding 1-C-phosphate was detectable neither in the cells nor in the surrounding medium. N-Nitrosamino-1-phosphates, unlike 1-glucuronides, therefore, do not seem to be important for nitrosamine toxicokinetics.

Animals↗
PubMed1990

Peroxidase-mediated reaction of the carcinogenic non-aminoazo dye 1-phenylazo-2-hydroxynaphthalene with transfer ribonucleic acid.

Horseradish peroxidase in the presence of hydrogen peroxide has the ability to mediate the activation of carcinogenic 1-phenylazo-2-hydroxynaphthalene (Sudan I) to DNA- and transfer RNA (tRNA)-bound products in vitro. tRNA is more accessible for modification by the activated carcinogen studied. tRNA modified by activated Sudan I becomes colored and has an absorption maximum of approximately 480 nm. Binding of metabolite(s) to tRNA is inhibited by ascorbate, glutathione, Mg2+ ions and nitrosobenzene. The mechanism of these protections was shown to be different for the different agents. tRNA modified by activated Sudan I exhibits a significantly increased acceptance for L-methionine. Enzymatic hydrolysis of modified tRNA with subsequent separation of nucleosides by HPLC suggests that the covalent modification of tRNA originating from the formation of more than one adduct with the nucleosides in tRNA is the predominant interaction of the activated Sudan I with tRNA.

Animals↗
PubMed1990

Mechanism of formation and 32P-postlabeling of DNA adducts derived from peroxidative activation of carcinogenic non-aminoazo dye 1-phenylazo-2-hydroxynaphthalene (Sudan I).

Horseradish peroxidase in the presence of hydrogen peroxide mediates the activation of carcinogenic 1-phenylazo-2-hydroxynaphthalene (Sudan I) to DNA-bound products in vitro. The peroxidase activating system is greater than 10 times more effective with respect to DNA modification by Sudan I than the microsomal enzymes containing cytochrome P450. The DNA-binding reaction of the Sudan I metabolite(s) formed by the peroxidase system is dependent on Sudan I and H2O2 concentration and pH. Reactive intermediate(s) or product(s) of the Sudan I oxidation by peroxidase with a short half-life are responsible for the DNA modification. DNA modified by peroxidase-activated Sudan I becomes colored and has an absorption maximum at approximately 480 nm. The modification of DNA by Sudan I metabolites(s) formed by the peroxidase system is inhibited by some compounds of physiological importance (ascorbate, glutathione, Mg2+ ions) and by radical trapping agents (nitrosobenzene, methyl viologen). 32P-Postlabeling assay of the DNA modified by Sudan I activated by the peroxidase system indicates that the covalent DNA adduct formation is the principal type of the DNA modification. Four major and several minor adducts of deoxyribonucleotide 3',5'-bisphosphate from DNA with Sudan I metabolite(s) were detected by the classical Randerath 32P-postlabelling assay as well as by the nuclease P1 version of the same method.

Animals↗
PubMed1990

Pharmacokinetics of N-nitrodimethylamine and N-nitromethylamine in the rat.

Oxidative metabolism of radioactively labeled N-nitrodimethylamine in rats was compared with that of N-nitromethylamine. Within 7 h, 20% of N-nitrodimethylamine was metabolized to CO2 but only 4% of N-nitromethylamine. The poor oxidative metabolism of N-nitromethylamine is also reflected in the blood levels determined after i.v. administration to catheterized rats. N-Nitrodimethylamine was cleared rapidly from rat blood, while N-nitromethylamine was rapidly distributed into body water but had a long elimination half-life. An amount equal to 5.2% of the dose of the monomethyl compound was excreted intact in urine, but only 0.004% of the dimethyl compound. The pharmacokinetic data obtained were compared with the published data on the pharmacokinetics of the structural analog N-nitrosodimethylamine.

Animals↗
PubMed1990

High-dose ifosfamide with mesna uroprotection: a phase I study.

Phase II trials of ifosfamide have been performed with standard doses of 5 to 8 g/m2/course. In this phase I study, 29 patients were treated with a 4-day continuous infusion ifosfamide to determine the maximum-tolerated dose and the nonhematologic dose-limiting toxicity. Autologous bone marrow support was to have been used for the subsequent dose level if granulocytes were more than 500/microL for more than 14 days in two of two to five patients at a given dose level. Doses were escalated from 8 to 18 g/m2 ifosfamide. Mesna was given at an equivalent dose by continuous infusion for 5 days. At the 18 g/m2 dose level, dose-limiting renal insufficiency and a median of 11 days (range, 8 to 18 days) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion ws not used. The duration of myelosuppression, the frequency and severity of mucositis, and renal tubular acidosis were all dose-dependent. Mild to moderate CNS toxicity also appeared to be related to dose; however, severe CNS toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. Transient hematuria (greater than 50 red blood cells [RBCs]/high power field) occurred once but did not affect treatment. There were nine responses (two complete) in 27 heavily pretreated assessable patients including seven responses in 20 patients with advanced refractory sarcoma. Ifosfamide with mesna uroprotection can undergo considerable dose escalation over the usual prescribed doses before nonhematologic dose-limiting toxicity is encountered. Ifosfamide has broad cytotoxicity against solid tumors and may prove to be an important addition to high-dose combination chemotherapy regimens.

Blood↗
PubMed1990

A phase I-II study of cyclophosphamide, thiotepa, and carboplatin with autologous bone marrow transplantation in solid tumor patients.

The principles of dose-response and combination chemotherapy were basic to the design of the initial curative standard-dose treatment regimens for leukemias, lymphomas, and testis cancer. Agents were selected with different dose-limiting toxicities, resulting in subadditive toxicity in combination. A fourth principle in the design of curative regimens was to combine agents with different mechanisms of action to avoid cross-resistance. Based on these principles, combinations of the highest tolerated doses of active noncross-resistant agents are required to decrease the emergence of drug resistance and achieve optimum cytotoxicity. Hematopoietic stem-cell support provides a mechanism for significantly increasing the doses of active agents, a strategy that has resulted in the cure of 10% to 50% of selected patients with lymphoma who could not be cured with standard-dose therapy. The lack of sufficiently effective cytoreductive conditioning regimens remains the major impediment to improving the high-dose therapy of patients with solid tumors. In this study, 27 patients with solid tumors were treated with a combination of cyclophosphamide, thiotepa, and carboplatin (CTCb) in a phase I-II study. Severe mucositis and neurotoxicity were dose-limiting. The maximum-tolerated dose (MTD) of the combination was 6.0 g/m2 of cyclophosphamide, 500 mg/m2 of thiotepa, and 800 mg/m2 of carboplatin. There were two deaths (7%) of sepsis, and an overall response rate of 72% in refractory tumors (81% in breast cancer). CTCb is a combination with low morbidity and high cytoreductive efficacy designed to exploit the principles of curative cancer chemotherapy.

Adult↗
PubMed1990

Preclinical studies relating to the use of thiotepa in the high-dose setting alone and in combination.

In vitro and in vivo studies with N,N',N''-triethylene-thiophosphoramide (thiotepa) alone and in combination with cyclophosphamide (CTX) were carried out using the MCF-7 human breast carcinoma cell line and the EMT6 mouse mammary carcinoma cell line. In vitro, survival curves were essentially linear. The cytotoxicity of thiotepa toward MCF-7 cells was markedly dependent on the presence of oxygen during the period of drug exposure, with a 3-log greater cell kill at 500 mumol with cells that were normally oxygenated compared with hypoxic cells. Incubation of thiotepa with an Aroclor 1254-induced rat liver S-9 homogenate in the presence of a reduced nicotinamide adenine dinucleotide phosphate-regenerating system resulted in an eightfold increase in cytotoxicity toward the MCF-7 cells over a wide range of drug concentrations. The thiotepa metabolite N,N',N''-triethylenephosphoramide (TEPA) was significantly less cytotoxic toward the MCF-7 cells than was thiotepa. Simultaneous and immediately sequential treatments with thiotepa and CTX produced supra-additive cell killing of both cell lines, although the magnitude of the supra-additivity was greater in the MCF-7 cell line than in the EMT6 cell line. These drugs Vppeared to be equally effective as thiol-depleting agents. By DNA alkaline elution, there was a pattern of increasing DNA cross-linking similar to the increasing levels of cytotoxicity of this drug combination as the concentrations of thiotepa increased. In the EMT6 tumor in vivo, the maximally tolerated combination therapy (5 mg/kg x 6, thiotepa, and 100 mg/kg x 3, CTX) produced about 25 days of tumor growth delay, which was not significantly different than expected for additivity of the individual drugs. The survival of EMT6 tumor cells after treatment of the animals with the various single doses of thiotepa and CTX was assayed. Tumor cell killing by thiotepa produced a very steep, linear survival curve through 5 logs with increasing dose. The tumor cell survival cure for CTX to 500 mg/kg had linear tumor cell kill through almost 4 logs. In vivo modeling of quasicontinuous exposure (3 intraperitoneal over 9 hours) versus pulse (single-dose) administration of thiotepa and CTX compared EMT6 tumor cell survival with survival of bone marrow as a representative sensitive normal tissue. With CTX, there was a considerable increase in the therapeutic index (killing of tumor cells/killing of colony forming units-granulocyte macrophage) when the same total dose of drug was administered in multiple injections versus a single injection. For thiotepa, smaller increases in therapeutic index were also observed with the multiple-injection schedule.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Quality of life in cancer patients: clinical considerations and perspectives.

Maintaining "quality of life" for a cancer patient is analogous to caring for the "whole" patient. Such care should include integration of multispecialty services, on-going patient education, attention to supportive care, and efforts to achieve organ preservation. Also to be taken into account are such factors as the extraordinarily heterogeneous backgrounds of cancer patients, the degree of involvement of the patient's family, and the financial implications of cancer and its treatment. These considerations require the primary physician and the rest of the care team to individualize their approach to each patient. All medical personnel must also realize that effective, honest communication may improve quality of life, even in those patients whose medical conditions are the poorest.

Attitude to Health↗
PubMed1989

Influence of schedule on alkylating agent cytotoxicity in vitro and in vivo.

High dose, multiple alkylating agent chemotherapy is being employed in conjunction with autologous marrow transplantation in the clinic. We have investigated the scheduling of several alkylating drugs in an effort to optimize their antitumor effects. In vitro modeling of "continuous" (up to 72 h) versus "bolus" (1 h) exposure in MCF-7 cells showed that for N,N',N"-triethylenethiophosphoramide (thiotEPA), cis-diamminedichloroplatinum(II) (CDDP), 4-hydroperoxycyclophosphamide, carboplatin, and L-phenylalanine mustard (L-PAM) "continuous" exposure yielded essentially the same killing kinetics as "bolus" exposure. For N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), however, even with fresh drug additions every 30 min, "bolus" exposure produced superior cytotoxicity. In vivo modeling of "continuous" (three i.p. injections over 9 h) versus "bolus" (single dose) administration of the alkylating agents cyclophosphamide, BCNU, thiotEPA, melphalan, CDDP, and carboplatin was conducted in mice bearing EMT6 tumors, and tumor cell killing as measured by tumor cell survival in vitro was compared with killing of bone marrow (CFU-GM) measured in culture as a representative sensitive normal tissue. With cyclophosphamide there was a considerable increase in the therapeutic index (killing of tumor cells/killing of CFU-GMs) when the same total dose of drug was administered in multiple injections versus a single injection. For BCNU and thiotEPA, smaller increases in therapeutic index were observed. With L-PAM and CDDP, some advantage to multiple versus single dose administration was observed, and for carboplatin a decrease in the therapeutic index was seen. In conclusion, for all six alkylating agents examined, the multiple dose schedule was at least as effective against the tumor as the single dose schedule at all dose levels.

Adenocarcinoma↗
PubMed1989

Evidence for enzymatic activation and oxygen involvement in cytotoxicity and antitumor activity of N,N',N''-triethylenethiophosphoramide.

The cytotoxicity of N,N',N''-triethylenethiophosphoramide (thiotepa) was studied in vitro in the MCF-7 human breast carcinoma cell line and in vivo using the EMT6 mouse mammary tumor model, under various conditions of oxygenation and in the presence and absence of Aroclor 1254-induced liver preparations. The cytotoxicity of thiotepa toward exponentially growing MCF-7 cells was markedly dependent on the presence of oxygen during the period of drug exposure, with 3 log greater cell kill at 500 microM thiotepa being observed when the cells were normally oxygenated compared with hypoxic cells. Incubation of thiotepa with an Aroclor 1254-induced rat liver S-9 homogenate, in the presence of a NADPH-regenerating system, resulted in an 8-fold increase in cytotoxicity towards the MCF-7 cells over a wide range of drug concentrations. Thiotepa was shown to be metabolized under these conditions in a NADPH- and O2-dependent reaction that was catalyzed by one or more microsomal cytochrome P-450 enzymes that were present in the S-9 fraction. The thiotepa metabolite triethylene phosphoramide, which hydrolyzes significantly faster than thiotepa, was significantly less cytotoxic toward the MCF-7 cells than was thiotepa itself, suggesting that it is unlikely to be the S-9 metabolite responsible for the observed increase in drug cytotoxicity. Moreover, triethylene phosphoramide cytotoxicity was only partially O2 dependent and was largely unaffected by incubation in the presence of the S-9 preparation, indicating a mechanism of action distinct from that of thiotepa. Tumor cell survival experiments with the EMT6 mouse mammary carcinoma system revealed that a 3.6-fold increase in thiotepa cytotoxicity was obtained by prior administration of the liver inducer Aroclor 1254 to the tumor-bearing animals, 5 days before drug treatment. Finally, the therapeutic effectiveness of thiotepa was significantly enhanced (3- to 5.8-fold increase in tumor growth delay) when an increase in oxygenation was achieved, by carbogen breathing, in animals given the perfluorochemical emulsion Fluosol-DA. These findings establish that the cytotoxic effects of thiotepa are oxygen dependent and may involve, at least in part, metabolic processes catalyzed by cytochrome P-450 enzymes.

Animals↗
PubMed1989

Metabolism of N-nitroso-hydroxyethyl-alkylamine phosphate esters in the rat.

The metabolism of 1-(N-methyl-N-nitrosamino)-ethylphosphate and 1-(N-ethyl-N-nitrosamino)-ethylphosphate in the rat was investigated. The determination of blood clearance, organ clearance, excretion of parent compounds in the urine and the exhalation of radiolabeled CO2 originating from a nitrosaminophosphate demonstrated a rapid metabolism of the compounds. The high activity of alkaline phosphatase in kidney caused a very rapid degradation of the nitrosamino phosphates in kidney homogenate, whereas the compounds were relatively stable in liver homogenate and serum. We, therefore, suggest a rapid degradation of such nitrosamino conjugates, if they are formed at all, in vivo.

Animals↗
PubMed1989

Selective expansion of 5,10-methylenetetrahydrofolate pools and modulation of 5-fluorouracil antitumor activity by leucovorin in vivo.

Expansion of CH2THF pools in tissues of BALB/c mice bearing s.c.-implanted EMT6 mammary adenocarcinomas was measured after leucovorin administration. Twenty-four mice were treated with leucovorin at doses of 0, 45, 90, or 180 mg/kg/injection x 8 injections spaced over 48 h. Tumor and bone marrow cytosols were assayed for CH2THF by forming ternary complexes with thymidylate synthase and [3H]FdUMP. Tumor CH2THF pools were expanded significantly at the two higher doses. Marrow levels were not different from controls. Groups of tumor bearing mice were treated with saline, leucovorin, 5-fluorouracil or 5-fluourouracil plus leucovorin on an optimal dosage schedule. Measured plus leucovorin on an optimal dosage schedule. Measured from the last day of treatment, these tumors grew to 10 mm root-mean-square diameters in 3.5 +/- 1.4, 5.0 +/- 1.2, 6.5 +/- 1.5, and 9.3 +/- 1.2 days, respectively. Growth rates were significantly different from controls only in the latter two groups.

Animals↗
PubMed1989

Effect of novobiocin on the antitumor activity and tumor cell and bone marrow survivals of three alkylating agents.

Our previous in vitro studies demonstrated marked synergy with alkylating agents when novobiocin was present during and after alkylating agent exposure. To determine whether this effect is observed in vivo, novobiocin was administered daily for 3 days prior to alkylating agent treatment, during alkylating agent treatment, and for 2 days after completion of alkylating agent treatment. When combined with cis-diamminedichloroplatinum(II), 1,3-bis(2-chloroethyl)-1-nitrosourea, or cyclophosphamide, there was significant enhancement of the growth delay of the FSaIIC fibrosarcoma implanted s.c. in C3H mice when compared with alkylating agents alone. In a second assay using ex vivo studies of tumor cells exposed in vivo, single doses of 100 mg/kg of novobiocin followed by cis-diamminedichloroplatinum(II) resulted in a 3- to 4-fold increase in tumor cell killing by cis-diamminedichloroplatinum(II). At a dose of 100 mg/kg of 1,3-bis(2-chloroethyl)-1-nitrosourea there was about a 7-fold increase in tumor cell kill upon addition of novobiocin. Cyclophosphamide showed a dose response effect with novobiocin, reaching 13-fold at a dose of 300 mg/kg of cyclophosphamide. In all cases bone marrow elements were affected less than were neoplastic cells, suggesting that the combination of novobiocin and alkylating agents may be a clinically useful strategy.

Alkylating Agents↗
PubMed1989

Neoadjuvant chemotherapy in marginally resectable stage III M0 non-small cell lung cancer: long-term follow-up in 41 patients.

Forty-one patients with marginally resectable stage III M0 non-small cell lung cancer (NSCLC) were entered into a study evaluating neoadjuvant cyclophosphamide, adriamycin, and cisplatin chemotherapy (CAP) followed by radiotherapy and subsequent resection. Postoperative radiotherapy and additional CAP were also administered. The objective disease regression rate prior to surgery was 72% (2 complete, 12 partial, and 7 minimal responses). Thoracotomy was carried out in 37 patients (90%), with resection of all gross disease in 36 patients (97%). Relapse occurred in 22 (61%) of the resected patients, involving chest only (four patients), chest and extra thoracic (nine patients), and extra thoracic only (nine patients). Subsequent CNS relapse developed in 9 (25%) of 36 postop patients in association with other sites of relapse (five patients) or as a solitary location (four patients). Only one of seven patients receiving prophylactic cranial irradiation (PCI) developed CNS relapse compared with 7 (26%) of 27 patients not receiving PCI. The median long-term follow-up for 14 living patients is 53+ months, with a rang of 38+ to 71+ months. Median survival for all patients is 32 months, with 1-year survival being 75%. The survival curve shows a plateau of 31% from 3 to 5+ years. Using a log rank test, no prognostic subgroups could be identified that significantly affected response rate, disease-free survival, or overall survival. While neoadjuvant CAP followed by radiotherapy appears to improve survival, more effective chemotherapy along with randomized studies are needed to determine the role of initial chemotherapy in marginally resectable NSCLC.

Adult↗