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PubMedDate not supplied

The effect of o6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair gene (hMLH1) status on the sensitivity to alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea(ACNU) in gallbladder carcinoma cells.

The aim of this study was to correlate O6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair gene (hMLH1) expression in gallbladder carcinoma cells with drug sensitivity to the bifunctional alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU). Using 5 gallbladder carcinoma cell lines and 1 colon carcinoma cell line (SW48), the MGMT and hMLH1 status was assessed both by RT-PCR and Western blot analyses. Sensitivity to ACNU was estimated by the MTT assay. MGMT+/hMLH1+ status was revealed in 2 gallbladder carcinoma cells, MGMT-/hMLH1+ in another 3 gallbladder carcinomas and MGMT-/hMLH1- in SW48. MGMT-/hMLH1+ and MGMT-/hMLH1- cells were more sensitive to ACNU compared with MGMT+/hMLH1+ cells. These results indicate that MGMT, but not hMLH1, expression is an important determinant for drug sensitivity to ACNU in gallbladder carcinoma cells. The drug effect of ACNU, which depends on the MGMT status, was verified using xenograft tumors grown in nude mice. Furthermore, the apoptotic index of MGMT- GB-dl xenografts was significantly increased by ACNU treatment, compared with that of MGMT+ KMG-C. In conclusion, the sensitivity to ACNU was not associated with hMLH1 status, but was found to depend only on the MGMT status. ACNU might be a useful chemotherapeutic agent for MGMT- gallbladder carcinoma, which is associated with poor patient outcome.

Adaptor Proteins, Signal Transducing↗
PubMed1991

A retrospective analysis of patients receiving surgery after chemotherapy for small cell lung cancer.

From 1984 to 1989, 20 of 142 patients with small cell carcinoma of the lung received surgery after intensive chemotherapy alone or chemotherapy combined with thoracic irradiation. All patients giving informed consent and having an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 were included in the present retrospective study. Ages ranged from 37-74 (median 58) years. All patients received 1-10 cycles of chemotherapy intravenously every three or four weeks (PVP: 80 mg cisplatin/m2, 100 mg etoposide/m2 x 3; CAV: 800 mg cyclophosphamide/m2, 50 mg doxorubicin/m2, 1.4 mg vincristine/m2, and other combinations) and were evaluated for surgery 1-27 months after the initial systemic chemotherapy. Clinically, two, three, eleven and for patients were diagnosed as having stages I, II, III and IV disease, respectively at the beginning of treatment. At the time of reevaluation after chemotherapy or chemotherapy plus chest radiotherapy there were one (5%) complete responder, 17 (85%) partial responders, and two (10%) with stable disease. Twenty patients underwent thoracotomy consisting of nine lobectomies and 11 pneumonectomies. Eighteen of the 20 had resectable lesions. According to postoperative pathological findings, there were six, one, seven and two patients with stages I, II, III and IV disease, respectively. In two patients no tumor was demonstrated pathologically. Small cell carcinoma was detected in 15 specimens and three had non-small cell carcinoma. Two of the 20 patients survived for more than five years. The median survival of the 20 patients was 22 months. It would appear that resection is applicable in only a selected subset of patients with small cell carcinoma of the lung.

Adult↗
PubMedDate not supplied

Results of chemo-radiotherapy and prognostic factors of small cell lung cancer.

We studied the therapeutic results and prognostic factors in 63 cases of small cell lung cancer (SCLC) experienced in our hospital over the past eight years. In the group initially treated with combination chemotherapy using COMP-VAD, the survival period was significantly prolonged. Use of adjuvant radiotherapy from the beginning had no effect on improvement in the survival period, but the period until local recurrences tended to be prolonged. Prognostic factors influencing survival were analyzed by the log rank test and generalized Wilcoxon test and multivariate analysis by the proportional hazard model of Cox. Statistical significance using univariate analysis was found for six factors (PS, clinical stage, LDH, albumin, treatment protocols, treatment response). The strong prognostic factors determined by multivariate analysis were, in the order of importance, chemotherapy protocol, initial PS, and treatment response.

Adult↗
PubMed1991

[Treatment of malignant gliomas by selective intraarterial infusion chemotherapy with high-dose ACNU and autologous bone marrow transplantation--preliminary report].

Six patients with malignant gliomas were treated by selective intracarotid infusion of ACNU at 15 mg/kg (about 600 mg per m2) or 10 mg/kg with or without radiotherapy and rescue of autologous bone marrow transplantation after surgery. These high doses of ACNU were well tolerated if bone marrow rescue was performed and granulocyte colony stimulating factor was used. With the development of microcatheters for use in selective intraarterial infusion, it has become possible to cannulate the major artery and infuse drugs at high dose into the artery feeding the tumor. The complication of ocular toxicity can be avoided by using the Tracker-18 or Balt (Magic) angiographic catheter. On the other hand, drug dosage and infusion rate must be chosen carefully, because of the increased likelihood of local arteritis and local necrosis caused by high dosage of ACNU. In the present study, local arteritis or cerebral infarction in the area of the middle cerebral artery was considered to have been prevented by extending the infusion time to 80 minutes. When combined with radiotherapy, 10 mg/kg of ACNU and 80 min. of infusion time were found to be optimal in relation to brain tolerance.

Adolescent↗
PubMed2006

[Glioma].

This chapter outlines the current clinical application of interferon for treatment of brain tumor, especially glioma. Since approved as a therapeutic drug for brain tumor originally produced in Japan, interferon-beta has been reported to be effective when it was used alone, in combination with chemo-radiotherapy (ACNU/MCNU as a nitrosourea derivative chemodrug, and radiation for 60 Gy totally). Recently, the regimen of combination with interferon-beta have been improved to obtain a higher efficacy rate. For example, as a fundamental study, temozolomide is an enthusiastic chemodrug to enhance the anti-tumor effect of interferon-beta when it is combined, pre-clinical and clinical trial will be scheduled. As for interferon-beta gene therapy by means of liposome as ad drug delivery system, already clinical trial has been performed and clinical safety and effectiveness have been proved, and it is expected that newly development in the field of gene therapy will be established and improvement of therapeutic results for malignant brain tumor will be achieved.

Antineoplastic Agents↗
PubMed1990

[Drug sensitivity test against malignant gliomas].

In treating brain tumors with chemotherapy, the choice of drug is most important since human tumors have different drug sensitivities and growth rates. We have been studying the therapeutic effect of anticancer drugs against malignant brain tumors in the following in vivo models. 1) Human glioma-bearing nude mice. 2) Methylcholantrene-induced 203Gl mouse glioma-bearing immunocompetent C57BL/6 mice. 3) Human gliomas transplanted into the chorioallantoic membrane of chick embryos. We evaluated the advantages of each model for anti-cancer drug sensitivity tests. 1) Human glioma-bearing nude mice were found to be most useful in predicting the direct effects of anticancer drugs. We evaluated the effects of several drugs such as ACNU or interferons in six glioma strains transplanted into nude mice. 2) Immunocompetent C57BL/6 mice models were found useful in predicting the therapeutic effects of biological response modifiers. In this model, we can also evaluate changes in immunological parameters such as NK activities or T cell subsets. 3) In the drug sensitivity test using the CAM of chick embryos, various kinds of gliomas could be grafted with a high rate of success. The tumor reduction rate of the sensitivity test using this system tended to agree with that using nude mice. This test was found to be useful in predicting the effect of drugs against gliomas directly resected from individual patients.

Animals↗
PubMed1991

[Multidisciplinary therapy using interferon and immunological evaluation for glioma patients: two-color analysis of T cell subsets].

We have employed IAR therapy [combination of postirradiation, chemotherapy and interferon (IFN)] for malignant glioma patients. Changes of lymphocyte fractions in patients were evaluated before and after IAR therapy, using a recently developed two-color analysis. Eight malignant glioma patients received irradiation, chemotherapy (ACNU) and immunotherapy (OK-432 and IFN-beta). Peripheral blood lymphocytes taken during hospitalization with IAR therapy (first half and latter half), and every 3 to 6 months for 2 years at the longest after IAR therapy were double-stained with FITC- and PI-labelled antibodies and two-color analysis was conducted by a FACS Analyzer. Six patients out of 8 survived for 6 months to 2 years, 2 died after 3 and 6 months, respectively. Leu-2a (suppressor/cytotoxic T), especially Leu-2a+ 15- (cytotoxic T) showed a high value. Leu-2a level decreased during treatment, and both Leu-2a+ 15- and Leu-2a+ 15+ (suppressor T) values decreased. Two thirds of the patients showing an increased Leu-2a+ 15+ level died. Leu 3a (helper/inducer T), especially Leu-3a+ 8+ (inducer T) level decreased, but Leu-3a+ 8- (helper T) level increased during treatment. The level decreased in the worse patients. Leu-3a/Leu-2a ratio was low, but it increased during treatment as compared with the results of conventional therapy. Leu-7, Leu-11a, NK activity, and gamma-IFN productivity were further studied. Treatment combined with IFN revealed an influence on the T cells resulting in an increase of helper T level and suppression of suppressor T level.

Adult↗
PubMed1991

Spergualin treatment-dependent delayed relapse of mouse T cell leukemia (DL812) after chemotherapy.

A transplantable mouse T cell leukemia, DL 812, is characterized by high sensitivity to 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-chloroethyl)-1-nitrosourea hydrochloride (ACNU) and intensive systemic infiltration. When subcutaneously inoculated, DL812 cells invade many organs and cause marked splenomegaly without forming local tumors. Disseminated DL812 leukemias are clinically completely cured by a single intraperitoneal injection of 1 mg ACNU, but more ACNU-resistant leukemias relapse immediately. A novel antitumor antibiotic, spergualin, is effective against various mouse leukemias. The effects of its analog with stronger anti-leukemia activity, 15-deoxyspergualin (DSG), on the relapse of DL812 leukemias after ACNU treatment were investigated. DDD mice were subcutaneously inoculated with 10(6) DL812 cells and intraperitoneally injected with 1 mg ACNU once on day 11 and with 100 micrograms DSG daily from day 12 on. The relapses were clinically completely suppressed for at least 30 days. Winn assays with spleen cells revealed that host immunity did not play a major role in maintenance of the clinical cure. Thus, when DSG treatment was discontinued after 15 or 30 daily injections, leukemias relapsed immediately. When it was extended to 50 daily injections, permanent cure was attained in 1 of 15 mice but relapses occurred under DSG treatment in the others. DSG is available for combined treatment of the leukemia. The current and previous results suggest that DL812 leukemias may serve as a model in study on immunochemotherapy of the disease.

Animals↗
PubMed1991

Altered O6-alkylguanine-DNA alkyltransferase activity in cell strains originating from mouse skin tumors induced by UV irradiation.

O6-Alkylguanine-DNA alkyltransferase (AGT) activity was assayed in the extracts of 47 cell strains originating from mouse skin tumors induced by UV irradiation. They were also examined for the sensitivity to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride by colony formation. The AGT activity (fmol/mg protein) of the tumor cell strains varied widely and the mean +/- SE was 72.5 +/- 9.37, while the AGT activity of the nontumor cell strains was 134 +/- 17. Among 47 strains, 6 strains showed extremely low or no AGT activity, about 5 fmol/mg protein or less, and were hypersensitive to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride. Long-term culture of the tumor cells did not change the AGT activity except in some strains which might have had coexisting normal cells in the population in early passages. All strains showed similar UV sensitivity regardless of AGT activity. This is the first report which demonstrates that about 13% of newly induced tumor cell strains are deficient in AGT activity similar to Mer-/Mex- phenotype that was found in approximately 20% of the established human tumor cell strains.

Animals↗
PubMed1991

[Effect of X-rays combined with ACNU and O6-ethylguanine on rat subcutaneous gliomas].

Rat gliomas of subcutaneously transplanted RGc-6 cells were irradiated with X-ray either alone, or combined with ACNU, and the cell-survival was assayed in vitro. Cell-survival curve composed of two components by X-irradiation alone indicated the presence of a hypoxic cell fraction. We have previously shown that combined treatment with ACNU apparently made the effect of X-ray on spheroids in vitro of the same cell line of RGc-6 more powerful. Although treatment of rat gliomas with ACNU administered at 2 hrs prior to X-irradiation was most effective, it resulted in only the additive effect of the independent action of the two agents. Further treatment by O6-ethylguanine prior to ACNU administration and X-irradiation apparently increased the strength of the effect of ACNU combined with X-ray to the dose-modifying factor for X-ray of 1.8. The result indicated that the combination of O6-ethylguanine prior to ACNU administration and X-irradiation may clinically enhance the effect of X-ray against apparent ACNU-resistant glioma cells such as RGc-6 cells.

Animals↗
PubMed1991

O6-methylguanine-DNA methyltransferase and human cancer chemotherapy.

Two kinds of human tumor cell strains having different activity of O6-methylguanine-DNA methyltransferase (O6-MT) were transplanted into nude mice. Then the mice were injected intraperitoneally with bifunctional alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). The tumors with low O6-MT activity were quickly suppressed or cured. The result suggests that some tumors, if provisionally determined with low O6-MT activity, might be efficiently cured by treatment with ACNU. This probably opens a new way for human cancer chemotherapy.

Animals↗
PubMed1991

Isolation of two chloroethylnitrosourea-sensitive Chinese hamster cell lines.

1-[(4-Amino-2-methylpyrimidin-5-yl)methyl]-3-(2-chloroethyl)-3- nitrosourea hydrochloride (ACNU), a cancer chemotherapeutic bifunctional alkylating agent, causes chloroethylation of DNA and subsequent DNA strand cross-linking through an ethylene bridge. We isolated and characterized two ACNU-sensitive mutants from mutagenized Chinese hamster ovary cells and found them to be new drug-sensitive recessive Chinese hamster mutants. Both mutants were sensitive to various monofunctional alkylating agents in a way similar to that of the parental cell lines CHO9. One mutant (UVS1) was cross-sensitive to UV and complemented the UV sensitivity of all Chinese hamster cell lines of 7 established complementation groups. Since UV-induced unscheduled DNA synthesis was very low, a new locus related to excision repair is thought to be defective in this cell line. Another ACNU-sensitive mutant, CNU1, was slightly more sensitive to UV than the parent cell line. CNU1 was cross-sensitive to 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and slightly more sensitive to mitomycin C. No increased accumulation of ACNU and a low level of UV-induced unscheduled DNA synthesis in this cell as compared with the parental cell line suggest that there is abnormality in a repair response of this mutant cell to some types of DNA cross-links.

Animals↗
PubMed1991

[Cooperative study of surgical adjuvant chemotherapy for colorectal cancer (third report): five-year results. Cooperative Study Group of Surgical Adjuvant Chemotherapy for Colorectal Cancer in Japan].

A randomized controlled study was carried out by the envelope method with 491 institutions in participation across the country in order to find an optimal surgical adjuvant chemotherapy for curatively resected colorectal cancer. The schedules for drug administration were different in four districts: ACNU + Futraful (FT) group and FT alone group in the Hokkaido-Shikoku district; the same schedule groups plus untreated group in the Chubu-Kinki district; MMC+FT group, FT alone group in the Tohoku-Kanto district; and ADM+FT group and FT alone group in the Chugoku-Kyushu district. The numbers of patients admitted to this study were 2,450 cases with colon cancer and 2,456 cases met the evaluation criteria of this study. The 5-year survival rate on the whole did not differ from combination therapy to single drug therapy in either colon cancer or rectal cancer, but in Dukes C rectal cancer the five-year survival rate tended to be higher with the combination therapies. In n2 (+) or a2(s) rectal cancer in particular, combination therapies with MMC and FT and with ADM and FT achieved significantly higher five-year survival rate, and the rate of local recurrence was significantly lower with ADM+FT.

Antineoplastic Combined Chemotherapy Protocols↗