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At least 1,009 records · Page 56Linked to original sources
PubMed1991

Release of N2,3-ethanoguanine from haloethylnitrosourea-treated DNA by Escherichia coli 3-methyladenine DNA glycosylase II.

3-Methyladenine DNA glycosylase II (Gly II), purified from Escherichia coli cells which carry the plasmid PYN1000, has been tested for its ability to release N2,3-ethanoguanine from DNA modified by the antitumor agent N-[2-chloroethyl-1,2-14C]-N'-cyclohexyl-N-nitrosourea ([14C]CCNU). Gly II has been shown to release N2,3-ethanoguanine in a protein- and time-dependent manner at a rate that exceeds the rate at which this enzyme releases other alkylated bases from [14C]CCNU-modified DNA. This finding widens the known substrate specificity for Gly II to include a modified base which bears an exocyclic ring structure, a class of modifications caused by a variety of chemical carcinogens.

Bacterial Proteins↗
PubMed1995

Repair of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea-induced damage by mammalian cell extracts.

The repair of damage induced by the alkylating antitumor drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was investigated using an in vitro excision repair system. Hamster cell extracts prepared from the parental CHO-9 cell line and the ERCC1 mutant 43-3B were both proficient in the repair of CCNU-induced damage. The in vitro repair of CCNU damage was faster than the repair of UV damage and plasmid substrates were rapidly and efficiently incised after incubation with either CHO-9 or 43-3B extracts. 7-Methylguanine (7-meG) and 3-methyladenine (3-meA) glycosylases were active to a similar extent in the CHO-9 and 43-3B extracts. The data indicate that most damage induced by CCNU is repaired via the ERCC1-independent base excision repair pathway, initiating with removal of chloroethylated and hydroxyethylated bases by N-glycosylases. Yet, the sensitive phenotype of 43-3B cells suggests that the ERCC1 gene product is required for the removal of a small subset of CCNU-induced lesions that are important for drug cytotoxicity.

Animals↗
PubMed1999

Mismatch repair, G(2)/M cell cycle arrest and lethality after DNA damage.

The role of the mismatch repair pathway in DNA replication is well defined but its involvement in processing DNA damage induced by chemical or physical agents is less clear. DNA repair and cell cycle control are tightly linked and it has been suggested that mismatch repair is necessary to activate the G(2)/M checkpoint in the presence of certain types of DNA damage. We investigated the proposed role for mismatch repair (MMR) in activation of the G(2)/M checkpoint following exposure to DNA-damaging agents. We compared the response of MMR-proficient HeLa and Raji cells with isogenic variants defective in either the hMutLalpha or hMutSalpha complex. Different agents were used: the cross-linker N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU), gamma-radiation and the monofunctional methylating agent N-methyl-N-nitrosourea (MNU). MMR-defective cells are relatively sensitive to CCNU, while no differences in survival between repair-proficient and -deficient cells were observed after exposure to gamma-radiation. Analysis of cell cycle distribution indicates that G(2) arrest is induced at least as efficiently in MMR-defective cells after exposure to either CCNU or ionizing radiation. As expected, MNU does not induce G(2) accumulation in MMR-defective cells, which are known to be highly tolerant to killing by methylating agents, indicating that MNU-induced cell cycle alterations are strictly dependent on the cytotoxic processing of methylation damage by MMR. Conversely, activation of the G(2)/M checkpoint after DNA damage induced by CCNU and gamma-radiation does not depend on functional MMR. In addition, the absence of a simple correlation between the extent of G(2) arrest and cell killing by these agents suggests that G(2) arrest reflects the processing by MMR of both lethal and non-lethal DNA damage.

Base Pair Mismatch↗
PubMed1988

Chemical specificity for induction of stress response genes by DNA-damaging drugs in human adenocarcinoma cells.

We investigated the induction of a stress response gene by anticancer drugs that damage and covalently modify DNA and other cellular macromolecules. Two human colon adenocarcinoma cell lines (HT-29 and BE) which differ in sensitivity to chloroethylnitrosoureas were treated with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) or with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Both of these drugs can alkylate, crosslink and carbamoylate cellular macromolecules. Treated cells were compared to controls for cytoplasmic levels of HSP70 RNA and for synthesis of heat shock proteins. We also tested for induction of stress response gene expression by equitoxic or greater concentrations of other nitrosourea analogues which can alkylate only, alkylate and crosslink only or carbamoylate only, as well as other DNA crosslinking agents (chlorambucil and cis-platinum). Of these, only BCNU and CCNU, the chloroethylnitrosoureas having all three of the macromolecule-modifying activities, strongly induce HSP70 RNA levels in a dose-dependent and time-dependent manner. Induction of HSP70 by BCNU occurred in both cell lines at dose ranges that were cytocidal to the BCNU-resistant HT-29 cells. No induction was seen in BE cells at the lower BCNU concentrations that were equitoxic to that more sensitive cell line. These observations suggest that induction of HSP70 by BCNU and CCNU is neither a direct consequence of DNA crosslinks nor an invariable result of cytocidal drugs.

Adenocarcinoma↗
PubMed1975

Graft versus leukemia. VI. Adoptive immunotherapy in combination with chemoradiotherapy for spontaneous leukemia-lymphoma in AKR mice.

A three-step treatment plan incorporating adoptive immunotherapy and chemoradiotherapy was used to treat AKR (H-2k) mice bearing spontaneous leukemia-lymphoma (SLL). 1) Leukemic mice were treated with chemoradiotherapy for immunosuppression and leukemia cytoreduction. 2) To introduce a graft-versus-leukemia reaction against residual malignant cells, the immunosuppressed AKR mice were given immunocompetent cells from H-2 mismatched DBA/2 (H-2d) donors. 3) To "rescue" the AKR hosts from incipient graft-versus-host disease, the mismatched DBA/2 cells were killed with combination chemotherapy, and cells from allogeneic H-2 matched RF (H-2k) donors were administered to restore hematopoiesis. Leukemic AKR mice thus treated had significant prolongation of their median survival time and a higher 60-day survival rate post treatment than did untreated controls, chemoradiotherapy controls, or control mice that received chemoradiotherapy plus cells from syngeneic donors. Therefore, adoptive immunotherapy may be useful as an adjunct to conventional therapy for treatment of SLL in AKR mice.

Amphotericin B↗
PubMed1976

The cause of G2-arrest in Chinese hamster ovary cells treated with anticancer drugs.

The nature of G2-arrest was studied in Chinese hamster ovary cells after exposure to 4'-demethyl-epipodophyllotoxin 9-)4,6-0-2-thenylidene-beta-D-glycopyranoside (VM26), 1,3-bis(2-chloroethyl)-1-nitrosourea, 1,3-cis(2-chloroethyl)-1-nitrosourea, cis-4[[[(2-chloroethyl)-nitrosoamino] carbonyl] amino]- cyclohexane carboxylic acid, or neocarzinostatin. To determine whether this G2-arrest was due to a metabolic block or to damage to the genetic material, we employed the phenomenon of premature chromosome condensation to visualize the chromosomes of the G2-blocked cells by fusing them with mitotic cells. The prematurely condensed chromosomes (PCC) of the treated cells were scored for their position in the cell cycle and the extent of chromosomal damage in the G2-PCC. The data revealed a significant enrichment of the G2-fraction in all the treatments. Most of the G2- PCC from the treated cells were extensively damaged, showing 10 or more breaks and exchanges per cell. These studies clearly indicated that the treated cells accumulated in G2-phase because of their failure to progress into mitosis as a direct or indirect result of the extensive damage to the chromosomes.

Animals↗
PubMed1978

Effect of phospholipids on maintenance of the cytotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in aqueous suspension.

Although the chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) is highly unstable in aqueous suspension, polar glycerophospholipids, notably phosphatidyl choline, had a protective action on the drug's cytotoxicity in aqueous suspension. The cytotoxicity of CCNU against C-6 glioma cells in monolayer culture was maintained longer when the drug was preincubated in the presence of phosphatidyl choline (0.5 mg/ml) than when it was preincubated in medium alone or with serum or when other phospholipids were added. Preservation of drug action may have been due to the formation of common micelles between CCNU and the phospholipid. The importance of the lipid interaction to the effectiveness of the nitrosoureas in vivo is unknown, but such interaction could be a factor in the duration of drug action, its access to the central nervous system, and its attachment to cell membranes.

Cell Survival↗
PubMed1978

Mutagenicity of nitrosourea compounds for Salmonella typhimurium.

The nitrosourea derivatives 1,3-bis(2-chloroethyl)-1-nitrosourea (NSC-409962), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; NSC-79037), 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Me-CCNU; NSC-95441), and 1-methyl-1-nitrosourea (MNU; NSC-23909) were screened for mutagenic potential with Salmonella typhimurium strains G46 and TA1530 in vitro and in vivo. Alu were also mutagenic in the host-mediated assay. Four additional chemotherapeutic nitrosoureas were tested in vitro, three of which were mutagenic. The lack of activity of the fourth agent was probably a reflection of its stability in solution rather than a true indication of mutagenic potential. All eight agents were tested in a repair test with S. typhimurium strains TA1978 and TA1538. Results of this test were negative, reflecting the insensitivity of these strains to ethylating and methylating agents. The insensitivity of the host-mediated assay is also discussed.

Carmustine↗
PubMed1988

Randomized trial of chemotherapy versus chemotherapy plus radiotherapy for stage I-II Hodgkin's disease.

A total of 277 patients with untreated Hodgkin's disease, clinical stages I-II, were randomized to cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP) alone for 6 monthly cycles or to CVPP plus radiation therapy (RT), 3,000 rad, to involved areas (CVPP plus RT). One or more of the following factors were considered as unfavorable prognosis: age greater than 45 years, more than two lymph node areas involved, or bulky disease. In the favorable group, disease-free survival (77% vs. 70%) or overall survival (92% vs. 91%) at 84 months for CVPP versus RT plus CVPP was similar. Patients with unfavorable prognosis treated with RT plus CVPP had longer disease-free survival (75% vs. 34%) (P = .001) and overall survival (84% vs. 66%) than patients treated with CVPP alone.

Adolescent↗
PubMed1992

Genotoxicity of tauromustine, a new water soluble taurine-based nitrosourea. I. Mutagenic and clastogenic activity of tauromustine in vitro.

Tauromustine (TCNU) a new taurine-based nitrosourea in phase III clinical trials against colon cancer, has been tested and compared with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (CCNU) for mutagenic potential in Salmonella typhimurium TA98 and TA100 and, for its ability to cause chromosome aberrations and sister chromatid exchanges (SCE) in human lymphocytes. A dose dependent increase in the number of mutations in S. typhimurium TA100 but not in TA98 was found from 1.6 to 1000 micrograms/plate for both TCNU and CCNU. In addition, in the presence of Aroclor activated liver microsomes, CCNU caused a further increase in the mutation frequency which was not found for TCNU. A dose dependent increase in the chromosome aberration rate in human lymphocytes was induced by both TCNU and CCNU at concentrations ranging from 3.75 to 30 micrograms/ml after 24 h treatment during the last cell cycle. When lymphocytes were treated in G0 both TCNU and CCNU induced a higher frequency of aberrations at 15 and 30 micrograms/ml than during the last cell cycle and, unexpectedly, chromosome-type, i.e. dicentrics appeared. The difference in the frequency of aberrations in these two phases may be related to the different levels of O6-methyl guanine transferase present in resting contra cycling lymphocytes. TCNU at 0.8-8 micrograms/ml also induced a dose dependent increase in the number of SCE in human lymphocytes. Neither the number of chromosomal aberrations nor the number of SCE were affected by the addition of 1000 micrograms/ml taurine to the culture medium.

Antineoplastic Agents↗
PubMed1988

Phosphotriester formation by the haloethylnitrosoureas and repair of these lesions by E. coli BS21 extracts.

The alkylation of phosphates in DNA by therapeutically active haloethylnitrosoureas was studied by reacting N-chloroethyl-N-nitrosourea (CNU) with dTpdT, separating the products by HPLC, and identifying them by co-chromatography with authentic markers. Both hydroxyethyl and chloroethyl phosphotriesters of dTpdT were identified; a similar reaction between CNU and dTR yielded 3-hydroxyethyl and 3-chloroethyl dTR as the major products of ring alkylation. A DNA-like substrate for repair studies was synthesized by reacting 14C-labelled N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (14C-CCNU) with poly dT and annealing the product to poly dA. An extract of E. coli strain BS21 selectively transferred a chloroethyl group from one of the chloroethyl phosphotriester isomers in this substrate to the bacterial protein; chemical instability of the hydroxyethyl phosphotriesters precluded definite conclusions about the repair of this product.

Alkylation↗
PubMed1991

Nearest neighbor effects on carcinogen binding to guanine runs in DNA.

A synthetic DNA fragment was constructed to determine the effect of 5' and 3' neighbors of guanine runs on the binding of chemical carcinogens. Determinations were made on the relative intensity of reactivity between aflatoxin B1 or benzo(a)pyrene and methylnitrosourea or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with various guanine positions in an endlabeled DNA fragment of known sequence. After reaction, the fragments were depurinated to produce strand breaks to allow Maxam and Gilbert sequencing for guanine positions. Relative reaction intensities were compared densitometrically. 3' neighbors exerted greater influence on carcinogen binding than did 5' neighbors, the influence extended only to the adjacent guanine and depended upon the chemical nature of the carcinogen. In addition, the presence of one carcinogen adduct in the guanine run influenced the formation of a subsequent adduct when the DNA was exposed to a second carcinogen, and this effect also depended on the nature of the second carcinogen. The results suggest that DNA adduct formation in the presence of multiple carcinogens is more complicated than an additive mechanism would suggest.

Aflatoxin B1↗