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At least 1,567 records · Page 87Linked to original sources
PubMed1983

Involvement of FMN and phenobarbital cytochrome P-450 in stimulating a one-electron reductive denitrosation of 1-(2-chloroethyl)-3-(cyclohexyl)-1-nitrosourea catalyzed by NADPH-cytochrome P-450 reductase.

Purified hepatic NADPH-cytochrome P-450 reductase, which was reconstituted with dilauroylphosphatidylcholine, catalyzed a one-electron reductive denitrosation of 1-(2-[14C]-chloroethyl)-3-(cyclohexyl)-1-nitrosourea ([14C]CCNU) to give 1-(2-[14C]-chloroethyl)-3-(cyclohexyl)urea at the expense of NADPH. Ambient oxygen or anoxic conditions did not alter the rates of [14C]CCNU denitrosation catalyzed by NADPH-cytochrome P-450 reductase with NADPH. Electron equivalents for reduction could be supplied by NADPH or sodium dithionite. However, the turnover number with NADPH was slightly greater than with sodium dithionite. Enzymatic denitrosation with sodium dithionite or NADPH was observed in anaerobic incubation mixtures which contained NADPH-cytochrome P-450 reductase with or without cytochrome P-450 purified from livers of phenobarbital (PB)-treated rats; PB cytochrome P-450 alone did not support catalysis. PB cytochrome P-450 stimulated reductase activity at molar concentrations approximately equal to or less than NADPH-cytochrome P-450 reductase concentration, but PB cytochrome P-450 concentrations greater than NADPH-cytochrome P-450 reductase inhibited catalytic denitrosation. Cytochrome c, FMN, and riboflavin demonstrated different degrees of stimulation of NADPH-cytochrome P-450 reductase-dependent denitrosation. Of the flavins tested, FMN demonstrated greater stimulation than riboflavin and FAD had no observable effect. A 3-fold stimulation by FMN was not observed in the absence of NADPH-cytochrome P-450 reductase. These studies provided evidence which establish NADPH-cytochrome P-450 reductase rather than PB cytochrome P-450 as the enzyme in the hepatic endoplasmic reticulum responsible for CCNU reductive metabolism.

Anaerobiosis↗
PubMed1983

Influence of polyamine depletion caused by alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, on alkylation- and carbamoylation-induced cytotoxicity in 9L rat brain tumor cells in vitro.

Using a colony-forming efficiency assay, we studied the effect of polyamine depletion on the cytotoxicity of four nitrosoureas with different capacities to alkylate and/or carbamoylate biomolecules. 9L rat brain tumor cells were treated with 10 mM alpha-difluoromethylornithine for 48 hr before a 1-hr treatment with nitrosoureas. The cytotoxicity of 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose, which alkylates and subsequently cross-links DNA but does not carbamoylate, was significantly increased by depletion of intracellular polyamines; the dose enhancement ratio of 1.3 is identical to that found for 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl-1-nitrosourea in previous studies. Addition of exogenous putrescine to polyamine-depleted 9L cells 24 hr before treatment prevented this phenomenon. In contrast, the cytotoxicity of 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea, which carbamoylates only, was significantly decreased in polyamine-depleted cells. This compound alone reduced intracellular polyamine levels. Polyamine depletion did not affect the cytotoxicity of the monoalkylating nitrosoureas N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea. Thus, polyamine depletion apparently potentiates the cytotoxicity only of chloroethylnitrosoureas that alkylate and cross-link.

Animals↗
PubMed1984

[10 years' use of ftorafur in tumor chemotherapy at the Robert Rössle Institute. A retrospective analysis from the clinical-toxologic point of view].

A retrospective analysis from the clinical-toxicological point of view Within a ten-year period a group of 130 patients treated with Ftorafur (FT) was selected randomly and 124 of these patients were evaluated with regard to therapeutic side effects using objective criterions. FT founded to be a therapeutic effective cytostatic drug with only a low level of therapeutic side effects. So FT seems to be combinable with more toxic cytostatics without additional serious toxicity for non-tumor tissues. The peroral FT-application was followed only by low graded side effects in comparison with a higher incidence after intravenous injection or infusion. Most observed FT side effects were: nausea and vomiting, toxic effects on the hematopoetic system and alopecia. No serious neurotoxic effects were observed.

Adult↗
PubMed1984

Effect of oxygen on misonidazole chemosensitization and cytotoxicity in vitro.

In order to assess the effect of oxygen on chemopotentiation by misonidazole (MISO), EMT-6/Ro tumor cells were exposed in vitro to combinations of CCNU and 1.0 mM MISO in culture medium equilibrated at various oxygen concentrations. The effect of oxygen on MISO cytotoxicity was similarly determined and compared with the relationship obtained for chemosensitization. MISO cytotoxicity and chemopotentiation were both oxygen sensitive, being maximal under anoxic conditions. Furthermore, the pattern of oxygen sensitivity was virtually identical for the two activities. These results suggest that a similar metabolic pathway, i.e., the oxygen-sensitive reduction of MISO to the nitroradical anion by cellular nitroreductases, is involved in the mechanism of both activities. The data further indicate that chemopotentiation can be expressed in cells treated at intermediate oxygen tensions. The implications of these findings with respect to the magnitude of chemopotentiation in vivo and the enhancement of normal tissue damage in animals treated with MISO and chemotherapy agents is discussed.

Aerobiosis↗
PubMed1984

Adjuvant therapy for carcinoma of the colon and rectum.

Because all types of cancer therapy are most effective when the tumor burden is small, adding adjuvant cancer treatment to surgical excision has great merit both in theory and experimentally. Even though large numbers of patients with large bowel cancer have been entered into various types of experimental trials over the past 25 years, the potential of multimodal cancer therapy has only been examined in a superficial manner at best. If this therapeutic approach had any substantial effectiveness, it would have long since become apparent. Surgical therapy is effective, with a five-year survival of 50%, and the various adjuvant therapies have shown only modest effectiveness when tested on patients with measurable disease. 5-Fluorouracil, with a response rate in measurable disease of approximately 20%, is the only consistently effective cancericidal drug, and its combination with other agents has thus far shown no increase in this response rate. Currently, available data would indicate a modest survival benefit from the use of postoperative 5-fluorouracil, particularly in patients with positive lymph nodes. There are a number of trials in progress studying the effectiveness of multiple drug combinations as well as combining chemotherapy with radiotherapy and/or immunotherapy in the adjuvant setting. Preliminary studies would suggest a benefit from infusing chemotherapy into the liver in the immediate postoperative period, although there has been no evidence substantiating improved survival from this approach. The multiple approaches for generating an effective immunologic response continue to be experimental and have little use in other than a highly controlled experimental environment. The use of radiotherapy as an adjuvant to surgery has been confined largely to patients with low-lying rectal cancer. There is substantial evidence that high-dosage radiotherapy for large bulky and fixed rectal cancer will result in shrinkage of the lesion, permitting more satisfactory surgical resection and decreasing the incidence of perineal recurrence. Evidence would also suggest that moderate-dosage preoperative radiotherapy may sufficiently alter cancer cells so that cells disseminated at the time of operation are no longer capable of growth. It has also been demonstrated that preoperative radiotherapy decreases the incidence of positive lymph nodes. Modest increase in survival following preoperative radiotherapy has also been demonstrated in numerous trials. Postoperative radiotherapy has not been tested for a sufficient period of time to either demonstrate its effectiveness or safety.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗
PubMed1976

Combination chemotherapy with three marginally effective agents, CCNU, vincristine, and bleomycin, in the treatment of stage III melanoma.

Forty-two patients with stage III melanoma were treated with a combination of CCNU, bleomycin, and vincristine. Seventeen of 35 evaluable patients achieved an objective response (48.5%) including five patients with CRs. The median duration of response was 4 months (range, 1-18 months). The responders had a median survival of 278 days (range, 78-1100 days) and the nonresponders had a median survival of 168 days (range 34-619 days). The toxicity off the combination was within an acceptable range with no toxic deaths.

Adolescent↗
PubMed1984

Hypomagnesemia after cisplatin combination chemotherapy.

Sixty-six patients receiving a five-drug combination chemotherapy regimen containing low-dose cisplatin were studied for the presence of hypomagnesemia. Thirty-eight (76%) of 50 patients receiving treatment every four weeks became hypomagnesemic during treatment. The incidence increased with the cumulative cisplatin dose, ranging from 41% after a single course to 100% of patients receiving six cycles of therapy. The incidence seemed lower in patients receiving the combination with a greater interval (eight weeks v four weeks) between cycles. We report the incidence and severity of hypomagnesemia to be dose dependent. The cause of the higher incidence of hypomagnesemia observed in this series compared with others is unknown but may be related to an interaction of cisplatin with another drug contained in this regimen.

Adult↗
PubMed1984

[3-year results of the combined treatment of stage I and II lymphogranulomatosis patients].

The authors present the results of the combined treatment (radiotherapy combined with 6 cycles of polychemotherapy using either the COPP or CVPP scheme) of 120 patients according to 4 programs differing in the volume of irradiation and intervals, between the cycles of polychemotherapy. The results of the study were compared to those of radiotherapy (irradiation of unilateral diaphragmatic and splenic lymph nodes) of 277 patients with Hodgkin's disease, Stages I--II. The combined treatment was shown to yield in better rates of a recurrence-free course of the disease and in slightly increased 3-year survival rates. It was shown that with identical drug therapy (6 cycles of polychemotherapy) the results of treatment in the groups of patients with different volumes of irradiation (irradiation of the clinically detectable foci of lesion only or of all the lymph nodes over the diaphragm and spleen) are rather similar. The results obtained indicate the advantages of the combined method of treatment of patients with Hodgkin's disease, Stages I--II. A reduced volume of irradiation seems possible in some cases.

Adult↗
PubMed1984

[Evaluation of the efficacy of radiotherapy in the combined treatment of generalized Hodgkin's disease in children].

An analysis of the results of treatment of 108 patients with Hodgkin's disease, Stage III, has shown a high efficacy of multiple modality treatment in children followed-up for 5 yrs. A comparative analysis of the results of the therapeutic programs (2 groups of patients) has shown advantages of the therapeutic program using COPP or CVPP chemotherapy programs for inducing remission which when combined with splenectomy and radiotherapy makes it possible to achieve 5-year survival in 86.6% of children.

Adolescent↗