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PubMed1987

[Hepatopathy with a progressive course after one-time administration of (chloro-2-ethyl)-1-cyclohexyl-3-nitroso-1-uréa (CCNU) in rats].

A few cases of liver involvement have been reported in patients receiving treatment with CCNU. Nitrosourea CCNU is an antitumoral agent largely used in the treatment of some types of leukemia, Hodgkin's disease, bronchial or cerebral tumors. It was shown that CCNU induced pericholangitis and intra-hepatic cholestasis in rat: moderate after 20 mg/kg CCNU, these hepatic lesions were maximal on day 8. In the present report we were interested in the evolution of hepatic alterations a long time after cessation of drug administration. So we studied hepatic ultrastructure three months after a unique 20 mg/kg or 50 mg/kg CCNU administration. Lesions were stable after 20 mg/kg CCNU and no reversibility was observed 3 months after 50 mg/kg CCNU: evolution to cholangiolysis, to adenomatous transformation of parenchyma or biliary cirrhosis were noted.

Animals↗
PubMed1986

Nature and biological significance of DNA modification by the haloethylnitrosoureas.

The haloethylnitrosoureas are both successful antitumour agents and laboratory carcinogens. A growing body of evidence suggests that their biological activities result from DNA modification. By decomposing in different ways, the haloethylnitrosoureas generate intermediates that can introduce either hydroxyethyl or haloethyl groups into DNA. One hydroxyethyl derivative, O6-hydroxyethylguanine, may be responsible for at least some of the carcinogenicity of these compounds. Haloethyl derivatives lead to cross-linked structures which may be cytotoxic. Two such cross-links, 1-(3-deoxycytidyl)-2-(1-deoxyguanosinyl)ethane (dCydCH2CH2dGuo) and 1,2-bis(7-guanyl)ethane (GuaCH2CH2Gua), have been isolated from DNA that has been reacted with haloethylnitrosoureas. Various DNA repair mechanisms, including O6-alkylguanine-DNA alkyltransferase, evidently play a role in modulating both the carcinogenic and cytotoxic actions of these agents.

Antineoplastic Agents↗
PubMed1978

Chemotherapy for colorectal cancer with 5-fluorouracil, cyclophosphamide, and CCNU: comparison of oral and continuous iv administration of 5-fluorouracil.

Forty-six adult patients with colorectal cancer were treated with cyclophosphamide and CCNU administered orally and 5-fluorouracil (5-FU) administered either orally or by continuous iv infusion (FCC-CIF), depending on the availability of hospital beds. The overall response rate in 37 patients with measurable disease was 25%. The response was greater in patients who had had no prior treatment (seven of 20 versus two of 17) and in patients treated with FCC-CIF (six of 19 versus three of 18). Among patients receiving FCC-CIF, response was also greater in those who had received no prior therapy (five of nine versus one of ten). The overall median survival was 7.5 months, regardless of the route of administration of 5-FU. Further investigations are indicated to study the efficacy of 5-FU administered by continuous iv infusion in combination with other agents in patients who have had no prior treatment.

Administration, Oral↗
PubMed1978

[A study of the use of sequential chemotherapy in 176 cases of glioblastoma (author's transl)].

Sequential administration of VM 26 and CCNU has been used in France for the treatment of glioblastoma since 1973. Results have shown that this association can cause a remission lasting, on average, from seven to eight months after starting chemotherapy. It seems that, adding Adriamycin to this sequential therapy does not increase its efficiency. On the other side, dosage and the interval between cycles of chemotherapy appear to be a determining factor in the activity, but the limits are very narrow. Therapy is either ineffective or has doubtful efficiency in about one third of patients, and even when prolonged clinical remission is obtained, cessation of therapy, usually due to a persistent thrombopenia is followed by progression of the tumour in the following months. The large amount of research being made in the field of cellular kinetics and pharcacology will, hopefully, lead to improvement in results.

Adult↗
PubMed1987

Enhancement of toxicity from N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea in V79 spheroids by a nitrofuran.

Hypoxic cell radiosensitizers enhance the cytotoxicity of several common chemotherapeutic agents in vitro and in vivo. Although this process has generally been called sensitization, few studies have documented true potentiation. We have used Chinese hamster V79 spheroids to study chemosensitization and fluorescence-activated cell sorting to specifically evaluate the roles of sensitizer binding and hypoxia in the effect. By using the median effect analysis to quantify the interactions of the agents, we conclude that marked potentiation can indeed be achieved. Somewhat greater potentiation was observed at increased depths within the spheroids, but the relative change was less than predicted on the basis of the decreasing oxygen tension. Further, increased toxicity did not necessarily lead to increased chemopotentiation, nor was potentiation directly related to the metabolism/binding of the nitrofuran. Thus, chemopotentiation is clearly a complicated process, highly dependent upon the sensitizer to antitumor drug ratio and the exposure conditions.

Animals↗
PubMed1986

Effect of cell cycle position on the survival of 9L cells treated with nitrosoureas that alkylate, cross-link, and carbamoylate.

The relationship between cell cycle position and cytotoxicity was studied in 9L rat brain tumor cells treated with nitrosoureas that, depending on their structures, can alkylate or alkylate and cross-link DNA and/or carbamoylate biomolecules. Because pure populations of G1-, S-, and G2-M-phase cells could not be obtained with the centrifugal elutriation methods used, drug sensitivity of cells in each phase of the cell cycle was estimated using a mathematical model that accounts for variation in enrichment of elutriated fractions. 1,3-Bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea, 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea, which alkylate and cross-link DNA and carbamoylate biomolecules, and 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlorozotocin), which alkylates and cross-links DNA but cannot carbamoylate biomolecules, killed more cells in G1 and G2-M phases than in S phase. N-Ethylnitrosourea, which alkylates and carbamoylates but does not form DNA interstrand cross-links, was more toxic to cells in S phase than in other phases. Cell kill caused by N,N'-bis(trans-4-hydroxycyclohexyl)-N-nitrosourea, a compound that carbamoylates only, increased progressively through the cell cycle from G1 to M. Nitrosoureas that cross-link DNA were more cytotoxic than nitrosoureas that do not cross-link DNA, although the latter had phase specificity. The results suggest that the increased sensitivity of G1- and G2-M-phase cells to chloroethylnitrosoureas is related to the formation of DNA interstrand cross-links.

Alkylating Agents↗
PubMed1986

Misonidazole-induced chemopotentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea toxicity in O6-methylguanine-DNA methyltransferase proficient (Mer+) and deficient (Mer-) cell lines.

The radiation sensitizing agent misonidazole (MISO) was combined with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) for the treatment of Mer+ (IMR-90, HeLa, and HeLa-S3) and Mer- (EMT-6/Ro, VA-13, and HeLa-MR) cell lines under hypoxic conditions in vitro. The magnitude of enhancement achieved by the addition of MISO was calculated by comparison with survival curves obtained by treating each cell line with CCNU alone, under hypoxic conditions. As expected, the Mer+ cells were more resistant to CCNU treatment than were their Mer- counterparts. In the presence of 1.0 mM MISO the toxicity of CCNU was enhanced (dose enhancement factor, 1.4-1.6) in all three of the Mer- lines. However, the Mer+ lines were less responsive to chemopotentiation by MISO. The toxicity of CCNU toward two of the Mer+ lines, IMR-90 and HeLa, was not modified by the addition of MISO, while a slight enhancement (dose enhancement factor, 1.2) was observed in the HeLa-S3 line. Similar results were obtained with IMR-90 and VA-13 cells treated by postincubation in which aerobic CCNU treatment was followed by hypoxic exposure to MISO for up to 6 h. While no correlation was observed between Mer status and the hypoxic toxicity of MISO, the data suggest that a relationship might exist between chemopotentiation and MISO sensitivity when each phenotype is considered separately. These observations suggesting that tumor cells of the Mer+ phenotype may be less responsive to MISO chemopotentiation have significant implications for ongoing and planned clinical trials designed to evaluate the potential of chemopotentiation using CCNU and MISO since greater than 75% of human tumors are Mer+.

Animals↗
PubMed1986

Prevention of 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl)ethane cross-link formation in DNA by rat liver O6-alkylguanine-DNA alkyltransferase.

Previous studies have shown that the haloethylnitrosoureas introduce the cross-link 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl)ethane into DNA. This structure is evidently formed by the following sequence of events: an initial attack of a haloethyl group on the O6 position of guanine, formation of the reactive intermediate, 1,O6-ethanoguanine, and reaction of this intermediate with deoxycytidine in the opposite DNA strand. To investigate the role of O6-alkylguanine-DNA alkyltransferase in preventing the formation of this cross-link, a DNA substrate containing O6-fluoroethylguanine has been prepared by reacting DNA with N-2-fluoroethyl-N'-cyclohexyl-N-nitrosourea. The O6-fluoroethylguanine content of this substrate decreases when it is incubated at 37 degrees C and pH 7.8 in the absence of repair factors because of the chemical instability of O6-fluoroethylguanine; however, this loss is accelerated by the addition of rat liver O6-alkylguanine-DNA alkyltransferase, indicating that this repair factor recognizes and repairs O6-fluoroethylguanine in DNA; furthermore, by using [chloroethyl-14C]N-chloroethyl-N'-cyclohexyl-N-nitrosourea, it can be shown directly that the addition of rat liver O6-alkylguanine-DNA alkyltransferase prevents 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl)ethane formation. These studies link the presence of repair activity to the prevention of a specific cytotoxic lesion in DNA.

Alkylation↗
PubMedDate not supplied

[Results of combined treatment (by surgery, ionizing radiation and the cytostatic drug CCNU) of patients with anaplastic glial neoplasms of the brain].

For estimating the effectiveness of combined treatment of cases of anaplastic gliomas of the cerebral hemispheres retrospective analysis was undertaken of 83 patients treated only surgically and prospective analysis of 81 patients treated by the combined method. In the group treated only surgically 47 patients had glioblastoma multiforme, and 36 had anaplastic oligodendroglioma. The general condition and the neurological status were evaluated using the score of Karnofsky. In the group of combined treatment the patients were given telegammatherapy from Co-60 cobalt source by the method of Skołyszewski and CCNU (Belustine) every 6-8 weeks for 1 year in doses of 100 mg/m2. In about 25% of patients transient leucopenia was observed, and 20% had transient thrombocytopenia. In about 30% of cases transient increase of intracranial pressure occurred. In the compared groups it was possible to establish, using the statistical method of representation probability of Kaplan-Meier and statistical analysis of Gehan as modified by Wilcoxon, that the mean survival time in the surgically treated patients was 6.25 months, while in the patients treated by combined method it was 13.97 months.

Brain↗
PubMedDate not supplied

[Effect of the method of treatment on mean survival time of patients with glial brain tumors].

In the years 1976-1981 54 patients were treated for malignant glial tumours confirmed by histological examination. The purpose of the reported analysis was a comparison of the mean survival time and the mean time of survival without evidence of recurrence in 3 groups of patients. In group I of 13 patients not treated surgically but receiving only conservative management the mean survival time was 7.4 weeks. In group II treated surgically but without other therapy this time was 29.2 weeks. In group III in which the patients were operated on and treated with chemotherapy and radiotherapy this time was 58.9 weeks. The differences between the groups were statistically significant. Similarly, the mean survival time without recurrence was significantly longer in the group receiving comprehensive treatment than in the group treated only surgically (46.5 vs 18.0 weeks).

Adult↗