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PubMed1985

[Evaluation of ACNU alone and combined with tegafur as additions to radiotherapy of the treatment of malignant gliomas--a cooperative clinical trial].

Controlled, prospective, randomized studies were performed to evaluate the effects of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3- (2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and ACNU plus tegafur as additions to radiotherapy for the treatment of malignant gliomas. In the first trial, 105 patients with glioblastoma or anaplastic astrocytoma were randomly divided into two groups after surgery and received radiotherapy (RT, 40 to 60 Gy to the whole brain), or radiotherapy plus concomitant chemotherapy with ACNU (100 mg/m2 on day 1 and 42). Effects of the treatment were compared in 82 evaluable patients from results of CT scans taken before and one month after the completion of radiotherapy. The regression rates more than 50% of the tumor size were observed in 15.0% of patients treated with RT alone and in 47.6% of patients treated with RT plus ACNU. The difference was statistically significant (p less than 0.005). In the second trial, 87 patients were randomly divided into two groups and received RT plus ACNU, or RT plus combined chemotherapy with ACNU and tegafur (400 mg/m2, daily for 8 weeks). Sixty-nine patients were within the valid study group. The regression rates more than 50% of the tumor size were observed in 34.2% of patients treated with RT plus ACNU: and in 41.2% treated with RT, ACNU plus tegafur. No statistical difference was noted in the response rate between the groups. These results indicate that ACNU is an effective agent in conjunction with radiotherapy for patients with malignant gliomas, and that tegafur does not enhance the effectiveness of ACNU.

Adolescent↗
PubMed1986

[Postoperative chemotherapy of pathological stage I non-small cell carcinoma of the lung].

Between August 1982 and February 1985, 13 patients with pathological stage I non-small cell lung cancer received postoperative chemotherapy with ACNU, ADM and 5-FU. Nine patients had squamous cell carcinoma, two adenocarcinoma, and two large cell carcinoma. All patients were alive in August, 1985, but four of them had recurrent disease. The site of recurrence was the brain in three and the contralateral lung in one. Of these four patients, three had t2n0(-) p0 squamous cell carcinoma and one t1n0(-) p1 large cell carcinoma. In a control group consisting of six squamous cell carcinoma and six adenocarcinoma, recurrence occurred in one patient with t1n0(-) p0 squamous cell carcinoma. Although the treated group had unfavorable conditions of cell type and tumor size, there was no evidence that this combination chemotherapy could control recurrence of the tumor under these conditions.

Adenocarcinoma↗
PubMed1986

[Combination chemotherapy and radiotherapy in small cell carcinoma of the lung].

Thirty-nine patients with small cell carcinoma of the lung were treated sequentially with induction chemotherapy, radiotherapy and then maintenance chemotherapy. Induction chemotherapy consisted of two regimens, cyclophosphamide, vincristine, methotrexate (COM) and adriamycin, ACNU, vindecine (ANV) given by randomization. Radiotherapy was given for patients with limited disease (LD) as a rule. After radiotherapy the drugs used for maintenance chemotherapy were alternated and reduced in dose. Eighteen patients were treated with a COM-ANV sequential combination and sixteen patients were treated with an ANV-COM combination. Thirteen patients had limited disease (LD) and eleven patients had extensive disease (ED). Of 12 patients with LD treated with COM-ANV therapy, 9 patients (75%) responded with 3 (25%) complete responses. Of 11 patients with LD treated with ANV-COM therapy, 9 patients (81.8%) responded to the therapy. According to disease extent, response rate was 82.6% for LD and 54.5% for ED. The median survival times were 9 months for patients with COM-ANV therapy and 12 months for those with ANV-COM therapy. Also, the median survival time was 15 months for LD patients and 5 months for ED patients. Major toxicities in ANV therapy were anorexia, nausea, and myelosuppression, and were more frequent than with COM therapy. These results showed no clear evidence of superiority in either the COM-AMV or ANV-COM regimen.

Adult↗
PubMed1986

[Treatment of malignant brain tumors with slowly releasing anticancer drug-polymer composites].

The purpose of this study is to present the methodology and results of a clinical trial of local chemotherapy of malignant brain tumors based on slowly-releasing anticancer drug-polymer composites. The slowly releasing drugs were prepared by combining and mutually dispersing anticancer agents with glassified monomers containing 10% polymetacrylic methyl acid and then this compound was frozen at -78 degrees C and exposed to 1 X 10(6) rad of gamma rays from cobalt 60. Thus we prepared a compound of polymers and anticancer agents. We used needle-shaped capsules of this compound. These capsules release the drug very slowly over 40 days. We administered locally to the malignant brain tumors with either slowly releasing mitomycin, slowly releasing adriamycin, slowly releasing ACNU or slowly releasing 5 Fu drugs. The following techniques were employed in implantation these capsules. Implantation into the remaining tumor wall at the time of excision. Implantation into the tumor by CT-guided stereotactic method. We implanted these drugs into tumor of 55 cases, thereafter we conducted both radiation and chemotherapy with ACNU in most patients. This method has the following advantages: It is possible to be employed to different types of anticancer agents. Both dosage and releasing time can be adjusted. It is possible to administer these capsules postoperatively by the stereotactic method. The clinical study consists of 55 patients, 20 cases of anaplastic astrocytoma, 23 cases of glioblastoma multiforme, 5 cases of oligodendroglioma, 3 cases of medulloblastoma and 4 cases of others. Survival rate estimated by Kaplan-Meier method was 47% in glioblastoma at 12 months and 91% in anaplastic astrocytoma at 18 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1987

[Treatment of autochthonous rat brain tumors with chemotherapy and radiotherapy].

The authors tried to establish a model of primary, autochthonous avian sarcoma virus-induced rat glioma for experimental chemotherapy and radiotherapy. It was found that the intracerebral inoculation of 2 X 10(6) FFU/5 microliter of an infectious cells-free homogeneous sub-group D Schmidt-Ruppin avian sarcoma virus into 3-day-old inbred Fischer rats induced brain tumors in all rats. The mean survival time of the inoculated rats was 58.7 +/- 12 days. With regard to the classification of the induced brain tumors in Fischer rats, astrocytoma accounted for 70%. This ASV-induced tumor in rats fulfills the following criteria for a desirable animal model. Spontaneously arising. Glial origin. Intraparenchymal growth. Uniformly fatal within a reasonable time period. In the present study, the therapeutic effects of anticancer drugs, such as ACNU and vincristine were evaluated and additionally, the effect of ACNU used in conjunction with radiation was also evaluated in this model. The mean survival time of rats was prolonged significantly with ACNU (20 mg/kg) or radiation therapy (1,000 rads), respectively, and in cases where ACNU was used together with radiation, the mean survival time was prolonged further still, but not very significantly, in comparison with radiation therapy alone. In conclusion, the ASV-induced rat glioma model was considered to be closely akin to a spontaneous brain tumor in terms of morphology, blood supply and kinetics of the primary tumor. Moreover, the therapeutic sensitivity of this model to anticancer drugs was fairly similar to that of human anaplastic astrocytoma. Considering these observations, this model seems to be an excellent experimental brain tumor model which is useful for evaluating the effect of new therapies against malignant brain tumors.

Animals↗
PubMed1988

[Role of autologous bone marrow transplantation in cancer chemotherapy].

Over the past 9 years, total number of 147 patients with various types of malignant solid tumors were treated 220 times with high-dose chemotherapy supported by autologous bone marrow transplantation. Two most frequently used chemotherapeutic protocols were: cyclophosphamide 1,600 mg/m2 + adriamycin 80 mg/m2 + ACNU 3 mg/kg and cyclophosphamide 1,600-2,400 mg/m2 + adriamycin 80 mg/m2 + CDDP 100-120 mg/m2. There were 89 patients with advanced and/or recurrent diseases. The overall response (CR + PR) rate was 44.1% with the complete response (CR) rate, being 11.8% among 68 evaluable patients in this group. The most favorable response was obtained in breast cancer patients with 77.3% response rate and 13.6% CR rate. Nearly 50% of patients with gastric, lung, gynecological and pediatric malignancies responded, whereas poor responses were observed in the cases of pancreato-biliary, colorectal, esophageal cancers and melanoma. In 8 complete responders, three are alive and well without any evidence of disease 5 years after the treatment. There were 58 patients who underwent this treatment in adjuvant settings. There are 5 patients with breast cancer who have been followed over 5 years after treatment. All of them are alive and well without any demonstrable diseases. Four of them were in stage IIIa and histologically examined axillary nodes were positive in 14/15, 11/17, 37/44, 22/25. Autologous bone marrow transplantation seems to be instrumental in shortening the period of myelosuppression, thus allowing safe dose escalation in chemotherapy. Adequacy of cryopreserved marrow as marrow inoculum was ascertained with mononuclear cell count, cellular viability, CFU-GM, CFU-E, BFU-E and CFU-Mk.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

[Studies on hyperthermia by the use of a thermosensitizing drug].

Hyperthermic treatment using ACNU combined with a thermosensitizing drug, methylglyoxal-bis-guanylhydrazone (MGBG), was studied in human gastric cancer xenotransplanted into nude mice. In order to increase the intra-cellular MGBG content, intraperitoneal injection of alpha-difluoromethylornithine(DFMO) 1000 mg/kg was performed twice with an interval of 6 hours and 50 mg/kg of MGBG was given at the time of the second administration of DFMO. After 6 hours of MGBG administration, ACNU 20 mg/kg was given intraperitoneally and, subsequently a 23-minute hyperthermia was carried out in a water bath at 43.5 degrees C. After 48 hours a second hyperthermia was performed by the same method. Tumor weight was estimated using Battelle's Columbus Institute protocol and the inoculated tumors, which were extirpated 60 minutes after 3H-thymidine injection at a prescribed interval after cessation of hyperthermia, were assayed biochemically for the determination of DNA biosynthesis. In mice given ACNU, DFMO, MGBG plus heat, considerably superior results were obtained. Although the DFMO plus MGBG group was inferior in antitumor activity to the ACNU only or heat only group, the DFMO, MGBG plus heat group showed much the same antitumor effects, compared to the ACNU plus heat group. These data suggest that the thermosensitizing efficacy of MGBG may be applicable for clinical use.

Animals↗
PubMed1986

[A case of massive fatal hemorrhage in a recurrent medulloblastoma during radiotherapy].

A medulloblastoma in a 7-year-old girl showed complete remission after the initial radiotherapy of 5,000 rad. But she had three episodes of recurrence in the cerebellum and in the spinal cord, and was treated by additional radiotherapy for the lesions 3,000 to 5,000 rad. When the total cerebellar tumor dose became 13,300 rad, a fatal intratumoral hemorrhage occurred. Autopsy revealed a massive intratumoral hematoma and thin-walled tumor vessels which might be designated as "sinusoid" or "telangiectasia" microscopically. The authors proposed a possibility that the thin-walled vessels and the high dose of radiotherapy caused the hemorrhage.

Cerebellar Neoplasms↗
PubMed1986

[A case of adult respiratory distress syndrome (ARDS) induced by radio-chemotherapy (RAFP therapy) of brain metastasis of stomach cancer].

A 77-year-old male was admitted to the hospital because of left hemiparesis secondary to multifocal cerebral metastases from adenocarcinoma of the stomach. He was treated with combination of radiotherapy and chemotherapy consisting of ACNU, Tegafur and PSK. He was in good condition, but abruptly developed severe dyspnea 40 days after administration of Tegafur and 28 days after that of ACNU. Chest X-ray at that time revealed diffuse opacity involving entire lung fields associated with marked hypoxia. The patient expired 9 days after this episode. The autopsy revealed acute interstitial pneumonitis associated with hyaline membrane formation consistent with adult respiratory distress syndrome involving entire lobes of both lungs without metastases. As to the etiology of the ARDS in this case, we concluded that the administration of Tegafur was the most likely as to the cause, although the possibility of betamethasone was not ruled out. The remaining factors were not likely as to the cause of the ARDS in this case.

Adenocarcinoma↗
PubMed1986

Reduction of pulmonary metastases of B16 melanoma by human recombinant interleukin 2 and lymphokine-activated killer cells in immunosuppressed C57BL/6 mice receiving anticancer agent.

The immunosuppressive effect of a water-soluble nitrosourea derivative, 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), was evaluated in terms of the cytotoxicity of spleen lymphocytes, and the restoring effect of lymphokine-activated killer (LAK) cells and/or human recombinant interleukin-2 (rIL-2) on the cytotoxicities of spleen lymphocytes was examined in ACNU-treated C57BL/6 mice. In addition, we tested whether the administration of LAK cells and/or rIL-2 could reduce the increased numbers of pulmonary metastases in ACNU-treated mice. The maximum effective dose of ACNU suppressed the cytotoxicity of spleen lymphocytes and pretreatment with ACNU enhanced the induction of artificial pulmonary metastases. The administration of LAK cells and/or human rIL-2 restored the cytotoxicity of spleen lymphocytes against YAC-1 and syngeneic B-16 melanoma cells in ACNU-treated mice, and these treatments partially suppressed the increased numbers of artificial pulmonary metastases of B-16 melanoma cells in ACNU-treated mice. These results are extremely important in providing a rationale for the introduction of adoptive immunotherapy using LAK cells and rIL-2 in patients with advanced cancer who are being treated with anticancer agent(s).

Animals↗
PubMed1986

[Combined therapy of polyamine antimetabolite and nitrosourea in human gastric cancer].

Antitumor therapy using the polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG), combined with ACNU was studied in human gastric cancer xenotransplanted into nude mice. DFMO 1,000 mg/kg (in two divided doses) and MGBG 50 mg/kg were given i.p. for 6 successive days from the time when the xenotransplanted tumor weighed about 100 mg, and ACNU 20 mg/kg was given i.p. every other day from the same time. Antitumor efficacy was assessed by the time course of tumor weight as well as of DNA biosynthesis and polyamine levels in tumor tissue. Tumor weight was estimated using Battelle's Columbus Institute protocol and DNA biosynthesis was assayed biochemically by 3H-TdR injection at a prescribed interval after termination of therapy. Furthermore, tumoral polyamine levels were assayed by HPLC. This three-drug regimen showed a favorable antitumor effect, compared to those of the other two therapies with DFMO plus MGBG as well as ACNU only. These data suggest that this combined regimen may have a synergistic efficacy judging from the action mechanisms of these three drugs.

Animals↗
PubMed1987

[Cooperative study of surgical adjuvant chemotherapy of colorectal cancer (first report): Investigation of background factors and adverse effects. Cooperative Study Group of Surgical Adjuvant Chemotherapy of Colorectal Cancer in Japan].

In order to evaluate the efficacy of surgical adjuvant chemotherapy in patients undergoing gross curative resection for colorectal cancer (excluding m and sm cancer), a randomized controlled study was conducted from January, 1982 to October, 1983. Four hundred and ninety-one institutions participated in this study. The schedules for drug administration differed according to each district. In the Hokkaido and Shikoku districts, the patients were divided into the following two groups, one was a combination of ACNU and Futraful (FT) and the other was FT only. In the Chubu and Kinki districts, three groups were studied, namely those receiving a combination of ACNU and FT, those receiving FT only and those given no adjuvant chemotherapy. In the Tohoku and Kanto districts, a combination of MMC and FT and administration of FT only were studied. In the Chugoku and Kyushu districts, the patients were divided into a combination of ADM and FT, and FT only group. Among the 3,926 registered cases, 3,421 cases were valid for the study. As to the background factors, there were no significant differences among the groups in each district. There were no significant differences in one-year survival rates and one-year disease-free rates. No serious adverse effects were observed in any of the groups.

Alopecia↗
PubMed1987

[A model for the sensitivity determination of anticancer agents against human cancer using nude mice].

Human tumors transplanted into nude BALB/c-nu mice have been used to test the sensitivity of the tumors to various anticancer agents. Three cancer cell lines from the stomach and one from the colon were transplanted into nude mice to establish a standard assay method for selection of effective drugs on individual tumors using the criteria of the Japanese Association of Sensitivity Determination for Carcinostatic Agents. From the LD values of anticancer drugs in nude mice, the appropriate doses of drugs were 6 mg/kg of MMC X 1(i.p.), 50 mg/kg of 5-FU q4d X 3 (i.p.), 120 mg/kg of CPA (i.p.), 30 mg/kg of ACNU (i.p.) 8 mg/kg of CDDP (i.p.) and 8 mg/kg of ADM (i.v.). At 3 weeks after initial treatment, the inhibition rate (IR) of the tumor was calculated from the formula IR = (1-T/C) X 100%, where T is the mean tumor weight of the treated group and C is the mean weight of the untreated group at that time. The tumors respond well to the anticancer agents when IR is more than 58%.

Adenocarcinoma↗
PubMed1987

[Results of combined radiochemotherapy of intracranial ependymoma].

Thirty patients with intracranial ependymoma were treated in our clinic from 1965 through 1984. They were 13 children and 17 adults. As for the location of tumor, 9 were in the lateral ventricle, 8 in the cerebral hemisphere, 12 in the fourth ventricle and one in the third ventricle. Histologically, 18 were benign and 12 were anaplastic. The clinical course was analyzed in 24 cases. Out of the 24 cases, surgical treatment with postoperative radiation therapy was done in 16 cases, surgical treatment with postoperative radiochemotherapy in 6, and radiochemotherapy alone in two. Five-year survival rate of patients treated by surgery with radiation therapy and with radiochemotherapy was 35.7% and 66.7%, respectively. Patients treated by surgery not only with radiation therapy but also with chemotherapy took a better outcome. Recurrence was observed in 9 cases. Four cases of the 9 were benign ependymoma. The recurrence was observed within 3 years after the initial treatment in all cases. Even if histologically benign, the recurrence occurred in a relatively high rate as reported in the past literature. It should, therefore, be stressed that the initial treatment is important not only for a malignant ependymoma but also for a benign one, and the postoperative radiochemotherapy is useful for the improvement of the results.

Adolescent↗
PubMed1987

[Results of supratentorial low-grade astrocytoma--effects of combined radiochemotherapy].

The retrospective analysis of 53 cases with supratentorial low-grade (grade 1 or 2 due to WHO grading) astrocytomas included the years 1965-84. The 5-year and 10-year survival rates were 61.9% and 52.1%, respectively. The recurrence of tumors occurred in 15 cases (28.3%), almost within 3 years after the initial treatment, and early recurrent cases indicated poor results. Among them, 6 cases were noticed increasing malignancy of histological findings. According to our investigations, the factors which influence to the survival rate were age of patients, duration of symptoms before treatment, presence of neurological deficits and degree of surgical removal of tumor. The patients with good prognosis were under 20-year old, over 6 months of duration, with no neurological signs and with total or subtotal removal. But, 5-year survival rate was not so improved by postoperative radiation therapy. Analysis on the effects of chemotherapy for low-grade astrocytoma was little reported. We treated 26 patients with RAFP therapy (Radiation + ACNU + FT-207 + PSK). Only 2 cases out of 26 showed the recurrence till now. The rate of reduction of their tumors was 46.2% by CT scan. So, it was considered that RAFP therapy was effective for supratentorial low-grade astrocytoma.

Adolescent↗
PubMed1987

Acquisition of resistance to 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride in V79 cells through increased removal of O6-alkylguanine.

The molecular mechanism of acquisition of resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride (ACNU) was investigated using ACNU-resistant clones (ACNUr-1-4) isolated from the V79 cell line. The binding level of alkyl cyanate, a decomposition product of ACNU, to protein in ACNUr-1 cells was not less than that in the parental V79 cells, indicating that the acquired resistance was not due to a reduced intracellular concentration of ACNU. Because O6-chloroethylguanine, an intermediate in cytotoxic interstrand cross-link formation by ACNU, is known to be repaired by the same mechanism as O6-ethyldeoxyguanosine (O6-EtdGuo), we quantitated O6-EtdGuo by radioimmunoassay at various times after exposure of cells to 100 micrograms/ml N-ethyl-N-nitrosourea for 20 min. In V79 cells, elimination of O6-EtdGuo was negligible, but in all four resistant clones, 30 to 59% of the O6-EtdGuo was removed within 24 hr after exposure. This increased removal of O6-EtdGuo among the resistant clones was associated with the activity of O6-alkylguanine DNA alkyltransferase (O6-AGT) determined using cell extracts. The present results indicate that increased removal of O6-chloroethylguanine in ACNU-resistant clones by O6-AGT is mechanistically linked to the acquisition of resistance to ACNU.

Animals↗
PubMed1987

O6-methylguanine methyltransferase activity and sensitivity of Japanese tumor cell strains to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)- 3-nitrosourea hydrochloride.

Using 40 tumor cell strains derived from various organs of Japanese tumor patients and also 12 normal cell strains, we have measured the activity of O6-methylguanine-DNA methyltransferase (MT), which can repair O6-methylguanine produced in DNA by alkylating agents. Then, the lethal sensitivities of the strains to the anti-tumor drug 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-)2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) were measured. The MT activity was assayed by measuring the 3H radioactivity transferred from the substrate DNA containing [methyl-3H]-O6-methylguanine to acceptor molecules in the cell extracts. Extracts from the majority of tumor strains and all normal cell strains contained substantial MT activity of varying degree, while the extracts of 6 tumor strains showed virtually undetectable MT activity. Hence these 6 strains were assigned as Mer-, the phenotype which is characterized by the inability to repair O6-methylguanine in DNA due to the lack of MT. The Mer- tumor strains were much more sensitive to ACNU than the rest of Mer+ strains, as measured by colony-forming ability. Furthermore, with all the tumor and normal strains tested, a good correlation was observed between MT activity and cellular resistance to ACNU. These results indicate that the frequency of Mer- strain is about 15% among Japanese tumor cell strains so far analyzed, and further suggest that MT may be the only system able to repair lethal DNA damage induced by ACNU.

Cell Survival↗