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At least 1,387 records · Page 77Linked to original sources
PubMed1988

Effect of O6-methylguanine on DNA interstrand cross-link formation by chloroethylnitrosoureas and 2-chloroethyl(methylsulfonyl)methanesulfonate.

Exposure of HT29 cells in culture to O6-methylguanine is known to result in a reduction in O6-alkylguanine-DNA alkyltransferase (AGT) activity and an enhancement of sensitivity to the cytotoxic effects of chloroethylating agents. Since cytotoxicity of these agents may be mediated by the formation of interstrand cross-links, alkaline elution analysis was performed on HT29 cells treated with 1-(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and Clomesone [2-chloroethyl(methylsulfonyl)methanesulfonate] in the presence or absence of O6-methylguanine pretreatment to determine if the enhanced toxicity was due to an increase in the number of cross-links formed. Interstrand cross-linking by 1-(2-chloroethyl)-1-nitrosourea or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea was increased by pretreatment with 0.4 mM O6-methylguanine for 24 h. Cross-linking by Clomesone was observed only in cells exposed to 0.4 mM O6-methylguanine for 24 h prior to administration of the drug and for 12 h after administration, suggesting that the resynthesis of the AGT may prevent the cross-linking by Clomesone. Complete recovery of AGT activity after reduction to 20 to 30% of the basal level upon treatment with 0.4 mM O6-methylguanine required between 8 h and 15 h in both HT29 cells and in Raji cells which were also sensitized to 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea by exposure to O6-methylguanine. These data suggest that the enhancement of chloroethylnitrosourea toxicity after treatment with O6-methylguanine may be related to an increase in the number of DNA cross-links and that the relatively rapid rate of AGT recovery plays a role in prevention of cross-links resulting from Clomesone.

Cell Division↗
PubMedDate not supplied

Chemotherapy induction, consolidation radiotherapy and maintenance alternating chemotherapy in small cell carcinoma of the lung.

Forty-four evaluable, previously untreated patients with small cell lung cancer were treated with two courses of induction chemotherapy consisting of POCC. Subsequently, all limited-disease patients and extensive-disease patients in CR received 4,000 to 5,000 cGy irradiation over 4 to 5 weeks (or the equivalent) to the primary tumor, mediastinum and supraclavicular areas and 3,000 cGy prophylactic cranial irradiation during 2 weeks. All patients received maintenance chemotherapy for a full year after CR or until disease progression. Eleven continued POCC while 33 received vinblastine, cyclophosphamide, and either adriamycin or methotrexate on an alternating schedule (VCMA). For the 20 limited-disease patients, the CR rate was 70% and the PR rate was 20%. Median survival was 22 months, local control was 62%, 2-year DFS was 35% and 3-year DFS was 20%. Of the 24 extensive-disease patients only 21% achieved CR and 54% achieved PR. Median survival was only 8 months and there were no disease-free survivors at 2 years. Toxicity was moderate with nausea and vomiting in all patients, and there were two deaths from myelosuppression in the group that received POCC maintenance therapy; there were no drug-related deaths in the VCMA group. Since these results are similar to those obtained with simpler regimes, we cannot recommend our regimen for the treatment of small cell lung cancer. The optimal treatment for this disease has yet to be elucidated.

Adult↗
PubMed1988

[Pathologic findings of small cell lung cancer (SCLC) after chemotherapy--analysis of 48 cases].

From 1980 to 1986, resected specimens from 48 SCLC patients after chemotherapy were studied pathologically. According to the pathologic changes, they were divided into four degrees: 1. The primary lesion disappeared and was replaced by fibrosis (6 cases, 12.5%); 2. Scanty residual cancer tissues were seen by microscopy (6 cases, 12.5%); 3. Degeneration and necrosis with fibrosis were present but active cancer tissues in small areas were found (18 cases, 37.5%), and 4. There was mild degeneration or no obvious changes (18 cases, 37.5%). Five specimens were examined by electron microscopy. The effect of chemotherapy in the primary lesion is more marked than that in the metastatic lymph nodes. The relationship between pathologic changes and response of chemotherapy and pathologic staging; comparison of clinical and pathologic staging and the prognosis of lymph node metastasis are discussed.

Adult↗
PubMed1987

Glutathione and related enzymes in rat brain tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea and nitrogen mustard.

Reduced glutathione (GSH) and activities of several glutathione-related enzymes were measured in two 9L rat brain tumor cell lines with differing sensitivities to both 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and nitrogen mustard. GSH, measured by a specific high-performance liquid chromatographic method, was found to be approximately twice as high in 9L cells sensitive to BCNU but resistant to nitrogen mustard. The nitrogen mustard resistant cell line was also found to have 2.5-fold more bulk glutathione transferase activity and approximately 3-fold more gamma-glutamyl transpeptidase activity. Glutathione reductase activity, protein thiol, and total protein content were similar in the two cell lines. Pretreatment of 9L cells with 50 microM buthionine sulfoximine for 24 h to deplete GSH only slightly potentiated BCNU cytotoxicity in a clonogenic assay whereas that of nitrogen mustard was markedly potentiated in both cell lines. Similarly, buthionine sulfoximine pretreatment had little effect on the induction of sister chromatid exchanges by BCNU, but significantly increased the number of sister chromatid exchanges induced by nitrogen mustard in both cell lines. Depleting GSH also had no significant effect on the cytotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea to 9L cells. Pretreatment of 9L cells with 1 mM GSH significantly protected against nitrogen mustard cytotoxicity. Moreover, nitrogen mustard incubated with GSH and glutathione transferase was 4-fold less cytotoxic than nitrogen mustard incubated with GSH alone. Incubation of BCNU with GSH alone or with glutathione transferase had no effect on BCNU cytotoxicity. These results indicate that elevated GSH and glutathione transferase activity is one mechanism of cellular resistance to nitrogen mustard in the 9L cell line, but it does not correlate with resistance to BCNU or other clinically important nitrosoureas.

Animals↗
PubMed1985

[Antineoplastic chemotherapy for bronchial carcinoma].

With the non small-cell bronchial carcinoma, the results of tumor chemotherapy are, on the whole, still unsatisfactory. It remains to be seen whether the more recent preparations, such as Cisplatin, VP16, Vindesine or combinations there of which are at present extensively investigated, will change this situation. The combinations: Cyclophosphamide/Doxorubicin/Methotrexate/Procarbazine, Cyclophosphamide/Doxorubicin/Cisplatin or Vindesine/Cisplatin are considered most prospective, were remission rates are reported to range from 30-40% with a mean period of remission from 5-7 months. Such values are approximatively reached also by monochemotherapy, e.g. Cyclophosphamide, Adriamycin or Vinblastine. Thus, radiotherapy combined, if necessary, with tumor chemotherapy continues to be the therapy of choice for the non small-cell bronchial carcinoma. Entirely different is the situation with the small-cell bronchial carcinoma. Here, with polychemotherapy being clearly superior to monochemotherapy, 80% of objective remissions are achieved with limited extension of the tumor, and 65%, with advanced tumor progression. The remissions may last here up to 18 months. Combinations of proven value are: Doxorubicin/Cyclophosphamide/Vincristine and VP16/Doxorubicin/Cyclophosphamide, with Cyclophosphamide being contained virtually in all proposed combinations as an essential component. Repeatedly proposed has also been the alternating application of non cross-resistant therapeutic schedules, e.g. VP16/Procarbazine and Cyclophosphamide/Lomustine/Vincristine/Procarbazine. For the inoperable small-cell bronchial carcinoma, chemotherapy is the therapy of choice. In how far additional radiotherapy will further improve the therapeutic results is now being intensively investigated. A high likelihood in this regard exists for a "prophylactic" irradiation of the CNS.

Antineoplastic Agents↗
PubMed1979

[Status and problems of the treatment of metastatic rectal cancer].

The results of chemotherapy in colorectal carcinoma are disappointing and therefore the treatment of metastatic rectal carcinoma, is problematic. 19 patients were treated with 5-FU, CCNU and Vincristin, the response rate was 26.3%, the median duration of remission 3.8 months.

Antineoplastic Agents↗
PubMed1985

[Chemotherapy and combined chemo- and radiotherapy of small cell lung cancer].

Objective response of small cell lung cancer to different modalities of chemo-and radiation chemotherapy was recorded in 68-94% while complete regression of tumor--in 22-50% of a total of 166 cases. Complete regression was registered in approximately 33% of cases of localized tumor process and in 16% of cases of expanded process. The survival median for different treatment modalities was 13.7-22.5 months in cases of complete regression and 8.7-12.4 months for partial regression. The cyclophosphamide + adriamycin + methotrexate treatment scheme proved effective in 87% of localized tumor (complete regression--27%). As a result of treatment with the said drugs plus radiation, objective response was obtained in 95%, with complete regression being registered in 68% of the latter group. Therefore, radiation should be an indispensable component of treatment for small cell lung cancer. A two year relapse- and metastasis--free period was observed in 18% cases of localized process and a five year period--in 9%.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Acute nonlymphocytic leukemia, preleukemia, and solid tumors following intensive chemotherapy of small cell carcinoma of the lung.

Six of 796 patients treated with intensive combination chemotherapy for small cell carcinoma of the lung developed overt acute nonlymphocytic leukemia (ANLL) (three patients) or preleukemia with severe refractory cytopenia and clonal cytogenetic abnormalities in bone marrow cells (three patients). The latent period to development of preleukemia or leukemia was less than two years in four of the six patients. The cumulative risk of preleukemia and leukemia according to a Kaplan-Meier estimate was 14.0% +/- 6.9% (mean +/- SE) four years after the start of treatment. The relative risk of overt ANLL was 77, since three cases were observed v 0.039 cases expected, based on the age- and sex-specific incidence of acute nonlymphocytic leukemia in the general Danish population. The risk of secondary solid tumors was not increased. The possible causes of the exceptionally early appearance and very high cumulative risk of leukemic complications found in the present study, as compared to previous experience in other malignant diseases, is discussed, including the implications for future therapy of patients with small cell lung cancer.

Acute Disease↗
PubMed1985

Small cell carcinoma of lung: a prospective clinical study.

Seventeen patients with small cell carcinoma of the lung diagnosed on sputum cytology, bronchial biopsy/aspirate or lymph node biopsy, were prospectively followed up for 33 months. Four patients who had no or inadequate treatment survived an average of 10.5 months. Ten treated patients survived 10.6 months. Three patients are still alive receiving chemotherapy with no local irradiation. All patients were Chinese; all smoked cigarettes; two patients were women; all patients were older than 50 years. Four patients had no chest complaints but presented with Superior Vena Caval obstruction (two cases), dermatomyositis and the Eaton Lambert syndrome. Two patients had the syndrome of inappropriate antidiuretic hormone secretion. None was hypercalcaemic. Twelve patients had right sided lung lesions. The majority of patients underwent combined radiotherapy and chemotherapy, the latter consisting of three weekly cyclical methotrexate, adriamycin, cyclophosphamide and CCNU (MACC regime).

Aged↗
PubMed1986

2-Chloroethyl (methylsulfonyl)methanesulfonate (NSC-338947), a more selective DNA alkylating agent than the chloroethylnitrosoureas.

The novel chloroethylating agent 2-chloroethyl (methylsulfonyl)methanesulfonate (CIEtSoSo) has been shown to act like the chloroethylnitrosoureas (CIEtNu's) in its DNA damaging and cytotoxic effects in human cell lines and has similar activity to the CIEtNu's in the National Cancer Institute antitumor screening tests. Its simpler chemistry, however, suggests that it may alkylate DNA more selectively than do the CIEtNu's. The DNA base adducts produced in calf thymus DNA by CIEtSoSo have been compared to a representative, non-carbamoylating CIEtNu, 1-(2-chloroethyl)-3-(cis-2-OH)cyclohexyl-1-nitrosourea, using high-pressure liquid chromatography. Two major modified base peaks were observed from the nitrosourea treated sample which have been subsequently identified by high-pressure liquid chromatography comparison of synthesized standards and by electron impact gas chromatography/mass spectrometric analysis to be 7-hydroxyethylguanine and 7-chloroethylguanine. In contrast only 7-chloroethylguanine was obtained from the CIEtSoSo treated DNA at equimolar doses. Thus CIEtSoSo was found to be more specific in its reaction with DNA in that it produced less variety of products than the nitrosourea, with no apparent generation of hydroxyethyl products, which are major side reactions of the CIEtNu's.

Alkylating Agents↗
PubMed1985

Chemotherapy of primary brain tumors.

This article covers chemotherapy of malignant astrocytomas, ependymoma, and medulloblastoma. The future direction of anticancer drugs is discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

DNA sequence selectivity of guanine-N7 alkylation by three antitumor chloroethylating agents.

The DNA sequence selectivities of guanine-N7 alkylation produced by three chloroethylating antitumor agents, 1-(2-chloroethyl)-3-(cis-2-hydroxy) cyclohexyl-1-nitrosourea (cis-2-OH CCNU), 2-chloroethyl (methylsulfonyl)methanesulfonate, and 8-carbamoyl-3-(2-chloroethyl)imidazo-[5,1-d]-1,2,3,5-tetrazin-4(3H )-one (mitozolomide), were examined using a modification of the Maxam and Gilbert sequencing technique. In a region of pBR322 DNA, 2-chloroethyl (methylsulfonyl)methanesulfonate produced approximately the same degree of alkylation at all guanines. cis-2-OH CCNU, however, preferentially alkylated the middle guanines in runs of three or more guanines; the intensity of the reaction increased with the number of adjacent guanines in the DNA sequence. Mitozolomide produced the same pattern of preferential alkylation but not as intensely as cis-2-OH CCNU. Three other nitrosoureas, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 1-(2-fluorethyl)-3-cyclohexyl-1-nitrosourea, and 1-(2-chloroethyl)-1-nitrosourea gave similar patterns of alkylation to that of cis-2-OH CCNU at pH 7.2. The ratio of 7-hydroxyethylguanine to 7-chloroethylguanine was approximately the same following treatment of the synthetic polymers dGn X dCn and (dG X dC)n with cis-2-OH CCNU, indicating that 7-chloroethylation and 7-hydroxyethylation were enhanced similarly by the presence of adjacent guanines. Ethylnitrosourea produced relatively little alkylation preference. The results suggest that the alkylating intermediates, 2-chloroethyldiazohydroxide and 2-hydroxyethyldiazohydroxide, tend to react preferentially with those guanine-N7 positions the electronegativity of which is enhanced by the presence of neighboring guanines. This is consistent with the presence of cationic character in the alkylating centers of these intermediates. 2-Chloroethyl (methylsulfonyl)methanesulfonate and ethyldiazohydroxide would not be expected to have strong cationic character, in agreement with their lack of sequence selectivity.

Alkylating Agents↗
PubMed1986

Effect of O6-alkylguanine pretreatment on the sensitivity of human colon tumor cells to the cytotoxic effects of chloroethylating agents.

Two human colon carcinoma cell lines which differ greatly in their content of O6-alkylguanine-DNA alkyltransferase were analyzed for their response to 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 2-chloroethyl(methylsulfonyl)methanesulfonate (ClEtSoSo) before and after treatment with O6-alkylguanines. HT29 cells contained about 17 times more alkyltransferase activity than BE cells. The alkyltransferase activity of HT29 cells was reduced by 60-80% by treatment for 24 h with 0.05-0.4 mM O6-methylguanine or O6-n-butylguanine. Such pretreatment prior to exposure to CCNU or ClEtSoSo increased the sensitivity of HT29 cells to these drugs. The exposure to O6-alkylguanines gave a greater enhancement of the toxic effects of ClEtSoSo than of CCNU. There was no significant increase in the toxicity of these agents towards the BE cells which contained much lower levels of the alkyltransferase. When added alone neither O6-methylguanine nor O6-n-butylguanine showed any toxicity towards HT29 or BE cells at the doses used. These results provide strong evidence that the formation of adducts at the O6-position of guanine by these agents contributes significantly to their lethality and that this reaction is more critical for ClEtSoSo than CCNU. The enhancement of the activity of chloroethylating agents by pretreatment with nontoxic doses of O6-alkylguanines may be clinically useful in terms of increasing their therapeutic efficacy towards cells containing high levels of alkyltransferase.

Carcinoma↗