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PubMed1989

[Comparison of surgical therapy and combined irradiation in rectal cancer--first report, effect of irradiation on the tumor. Study Group of Surgical Therapy and Combined Irradiation in Rectal Cancer].

In order to establish the best protocol for the treatment of rectal cancers, a cooperative study on preoperative radiation therapy was conducted by 44 institutions in eastern Japan. A total of 166 cases that did not receive preoperative chemotherapy were analyzed, and the following conclusions were obtained. A comparison between two groups of patients, one that had received preoperative irradiation and the other that had not, revealed remarkable tumor regression in the former along with reduction of in rectal stenosis, condition of the border of the lesion, bleeding, constriction and central excavation. There were no significant differences between the two groups in terms of lymph node metastasis. Histological examination based on the criteria established by Oboshi and Shimosato showed radiation effects better than grade II b in 32.1% primary tumors and in 33.3% of metastatic lymph nodes within the radiation field. No significant differences in the incidence of side effects or complications were noted between the two groups.

Adult↗
PubMed1989

[Chemical modifiers in radiotherapy].

The halogenated pyrimidine analogue bromodeoxyuridine (BrdU), which is incorporated into nuclei during DNA synthesis, has long been known to be a radiation sensitizer. Since 1965, BAR therapy (BrdU-antimetabolite-radiation therapy), in which BrdU was administered intraarterially as a radiosensitizer, has been applied to patients with malignant gliomas and the improvement in survival rate within two years has been reported. Recently, intravenous infusion of BrdU has prove to be sufficiently effective as a radiosensitizer and BrdU is still being utilized as a chemical modifier for patients with malignant gliomas. Misonidazole was developed as a hypoxic cell sensitizer and was expected to enhance the radiation response of malignant tumors. However, the clinical trial of misonidazole in patients with brain tumors showed little clinical benefit of this agent as a radiosensitizer, and therefore it is no longer used in the treatment of malignant gliomas. Synchronized chemoradiotherapy, in which alkaloid and alkyl agents are used to accumulate cells into the radiosensitive G2 and M phases, was developed for the treatment of malignant gliomas in 1976 and significant improvement in survival has been reported. However, phase II studies demonstrated that radiotherapy with alkyl agents such as BCNU and ACNU did not prolong the survival of patients with malignant gliomas as compared with radiotherapy alone, although they did increase the response rate. Since 1985, the Brain Tumor Interferon Study Group has clinically applied one of the biological response modifiers (BRM), interferon-beta (INF-beta) as a chemical modifier in patient with malignant gliomas. They have reported that the response rates in patients treated with ACNU + radiation and INF-beta + ACNU + radiation were 19.6% and 41.2%, respectively. Their results suggested that IFN-beta with ACNU was a promising regimen as a chemical modifier in radiotherapy for patients with malignant gliomas. In order to improve the rate of local control of malignant gliomas and to prolong the survival of patients, it is necessary to continue to seek effective chemical modifiers including BRMs, as well as to develop irradiation techniques.

Brain Neoplasms↗
PubMed1989

[Response to antitumoral agents of a human medulloblastoma implanted into the chorioallantoic membrane of a chick embryo].

In a previous study the authors have reported on a correlation between the effects of drugs on gliomas grown in the eggs and in the nude mice, and in this study, they have observed the antineoplastic effects of ACNU or combined chemotherapy (CAP-cyclophosphamide, adriamycin, cisplatin) against a medulloblastoma applied onto the chorioallantoic membrane (CAM) of a chick embryo. In this model, ACNU was thought to be ineffective because of an intracerebral dissemination that occurred in spite of the administration of ACNU. ACNU also proved ineffective against the medulloblastoma that grew on the CAM. There seemed to be correlation between the results of this test and the clinical course of this model. Thus this sensitivity test is thought to be useful in the screening of drugs against gliomas.

Adolescent↗
PubMed1989

[Antitumor efficacy of FK 973 on malignant glioma cells].

FK 973, a new substituted dihydrobenzoxazine, was obtained by chemical modification of a novel antibiotic which was isolated from the fermentation products of streptomyces sandaensis No. 6897. FK 973 had cytotoxic effects against in vitro cultured human and murine glioma cells. The concentration of FK 973 required to inhibit cell growth by 50% was 0.06-5 micrograms/ml, after 2-day exposure of this drug against human glioblastoma (ONS-6, 12, 23, and ONS-12/ACNU), human medulloblastoma (ONS-76, 81), human neuroblastoma (ST), and murine glioblastoma (RSV-M glioma). FK 973 showed antitumor efficacy in the meningeal gliomatosis models by RSV-M glioma cells. The median survival time (MST) of models treated by FK 973 (i.t.) was 30 days. However, the MST of control group was 23 days. In the in vitro neurotoxicity test, FK 973 proved to be slightly more toxic than ACNU and MTX, but it had no crucial problems, compared with ADM.

Animals↗
PubMed1987

[Controlled multimodality treatment of brain stem gliomas].

Thirty-eight children were diagnosed as having a brain stem glioma at Nagoya University. Thirty-three patients in our previous series from 1957 to 1983, were treated traditionally with radiation and at late stage with shunting operation for hydrocephalus and/or suboccipital decompression, but not with direct operation for tumors. In general, tumors constantly grew regardless histology and their mean survival time was only 7.0 months even with transient neurological remission. On the other hand, recent five patients since 1984 were treated with prospective multimodality treatment. According to neuroradiological studies by X ray and/or NMR, CT scanning, the brain stem glioma cases were classified into subgroups of intrinsic and exophytic. Then the former were treated non-surgically with adjuvant therapy of Interferon-ACNU-Radiation (IAR) and the latter were treated surgically at first by resection of the tumor followed by adjuvant therapy of IAR or interferon-CDDP. Four out of five patients responded to adjuvant therapy (complete response = 2, partial response = 2, response rate = 80%) and they are all alive after 7-28 months follow-up period. It is concluded from our results that CT scanning can diagnose the accurate location and nature of brain stem gliomas, surgical therapy benefits at least in exophytic cases, and IAR adjuvant therapy may prolong the survival time of patients.

Adolescent↗
PubMed1988

[Randomized comparative study of CE (CDDP plus etoposide) and CE-AVN (ACNU, VCR plus procarbazine) as combined anticancer chemotherapy in small cell cancer of the lung].

A randomized comparative study of anticancer chemotherapy CE (CDDP plus etoposide) and CE-AVN (ACNU, VCR plus procarbazine) was carried out on 27 patients with small cell lung cancer (SCLC) without previous chemotherapy. In CE therapy, 12 patients received injection of CDDP (80 mg/m2 on day 1) and etoposide (75 mg/m2 on day 1-5) every 4 weeks (Protocol 1). Fifteen patients received 2 courses of CE and 1 course of AVN therapy (ACNU 100 mg/m2 on day 1, vincristine 0.7 mg/m2 once a week and procarbazine 50 mg/day, daily) for 6 to 8 weeks (Protocol 2). One patient (8%) and 2 patients (20%) achieved complete response with Protocol 1 and 2, respectively. Seven patients (58%) and 9 patients (60%) achieved partial response with Protocol 1 and 2, respectively. The median survival time (MST) was 12 and 14 months, and duration of remission was 4.5 and 7 months in patients treated with Protocol 1 and 2, respectively. No significant difference in MST and duration of remission in each group was observed. However, 2 patients (13%) treated with Protocol 2 survived more than 3 years. Both protocols were well tolerated with only moderate gastrointestinal symptoms, mild bone marrow toxicity and alopecia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

[The role of radiotherapy in small cell lung cancer].

From 1974 to 1984, we have treated 70 patients with SCLC using radiotherapy (RT) alone or in combination with chemotherapy (CT). It was demonstrated that a heavy CT regimen causing a severe toxicity did not always cause good results. On the other hand, there was a long-term survivor in those patients who were treated with RT alone. Considering from our results as well as from reviews of literatures, it is evident that RT can reduce a significant number of local relapses but has little effect on systemic disease. Therefore, RT added to CT seems to improve a long-term survival specifically in those patients in whom CR is induced from CT. The characteristics of the long-term survivors treated with combined treatment are: limited disease, thoracic RT, good PS, only single site of metastases. In conclusion, there is no doubt that CT plays an important role in the management of SCLC. However, its efficacy is still far from desired, and a new type of CT is warranted.

Carcinoma, Small Cell↗
PubMed1988

[Treatment of malignant gliomas with high-dose ACNU and autologous bone marrow transplantation].

Two patients with malignant gliomas located in the frontal lobe were treated by supraophthalmic intracarotid infusion of high-dose ACNU 15 mg/kg (ca. 600 mg/m2) combined with a total 60 Gy of irradiation after surgery. Irradiation therapy was started 13 days (case 1) and 10 days (case 2) after surgery, and single chemotherapy with ACNU 1,020 mg (case 1) and 1,100 mg (case 2) was performed when 36 Gy of whole brain irradiation was done. Chemotherapy was followed by autologous bone marrow transplantation containing 6.8 X 10(9) and 8.9 X 10(8) nucleated cells, respectively. Nadirs of white cell counts on 9 days in case 1 and 14 days in case 2 after chemotherapy were 280 cells and 240 cells/mm3, respectively, and the white cell counts less than 1,000/mm3 continued for 7 and 12 days, respectively. Local irradiation was started again when the number of white cells became more than 1,000/mm3 and 24 Gy was completed in each case. CT scanning carried out on discharge demonstrated no apparent abnormal high density area by contrast medium in both cases. These two patients did not show severe side effects at 10 months in case 1 and at 3 months in case 2 after high dose ACNU therapy, and remained progression-free at that time. Dose 15 mg/kg of ACNU may be the maximum tolerable dose patients can recover from severe myelosuppression, caused by high dose ACNU therapy combined with irradiation therapy, by marrow rescue.

Antineoplastic Agents↗
PubMed1989

[Circumvention of ACNU-resistance in rat glioma cells by pretreatment with O6-methylguanine].

The chemotherapy of malignant brain tumors has been, only partially successful yet. Recently major concern is drug resistance, one of possible mechanisms of such drug resistance stems from inducible repair enzyme, especially in case of chloroethylnitrosoureas as ACNU or BCNU. We examined the changes of acquired resistance to ACNU in rat glioma cells by pretreatment with O6-methylguanine, which is a substrate for O6-methylguanine methyltransferase. ACNU-resistant (9L/AC) cells had established after 10 times treatments of ACNU. 9L/AC cells were pretreated with 2 mM O6-methylguanine for 2 hours, and subsequently challenged with increasing doses of ACNU for 2 hours. In vitro colony formation assay the survival fraction of 9L and 9L/AC cells ranged from 0.39 to 0.63 by 2-hour reaction of 1-3 mM O6-methylguanine. Based on the dose-response curve for ACNU in 9L/AC cells, by O6-methylguanine pretreatment (2 mM), ACNU-resistance decreased markedly to one-third, one-fifth, and one-two hundredth at 12, 24, 36 microM ACNU, respectively. In contrast, the survival of 9L cells against ACNU was similar under O6-methylguanine pretreatment or nontreatment condition. Therefore, ACNU-resistance is considerably related to DNA repair enzyme induction, and the substrates may potentiate the cell-killing effect of ACNU in the resistant glioma cells.

Animals↗
PubMed1987

[Effects of derivatives of Ara-C, 5-fluorouracil and nitrosourea against intracerebral implanted L1210 leukemia].

The effects of Ara-C derivatives, 5-FU derivatives and water-soluble nitrosoureas on L1210 leukemia implanted intracerebrally have been evaluated. Daily treatment with BH-AC showed a similar effect to that of Ara-C and intermittent treatment with BH-AC showed a marked effect. Daily treatment with FT-207, UFT and HCFU, 5-FU derivatives, resulted in more than 50% ILS but the effects of these compounds were inferior to those of ACNU and BH-AC. MCNU, a water-soluble nitrosourea, was effective, but less so than ACNU.

Animals↗
PubMed1987

[Evaluation by multiple regression analysis of factors influencing the chemosensitivity of human tumors xenografted into nude mice].

The chemosensitivity of human cancer lines is thought to be expressed as a result of contributions by various interacting factors. Multiple regression analyses were performed in order to clarify the weighting of factors responsible for the chemosensitivity of 15 human cancers xenografted into nude mice. Inhibition rates of 11 anticancer agents predetermined for each line of human cancer were used as the criterion variables. As the explanatory variables, 9 parameters characteristic of each cancer or cancer-bearing mouse were selected as follows; grade of differentiation, vascularity, percentage necrosis, volume doubling time, labeling index, LDH activity, tissue/serum LDH ratio, thymidine phosphorylase activity and serum CEA. By applying this analysis with stepwise deletion, the estimated multiple regression equations for drug sensitivity were clarified for each drug. Although all equations were composed of different factors and their partial repression coefficients varied from drug to drug, those among analogous drugs such as FT-207 and UFT, or MMC and M-83 had similar factors. The equations for M-83, ACNU and ADR consisted of a number of parameters with a sufficiently high coefficient of determination of over 80%. Even in cases of MXT that showed no significant factor upon simple correlation analysis, an equation with 7 factors revealed a coefficient of determination of 0.83. The estimated values of effectiveness for these drugs showed remarkable coincidence with each actual value. For some drugs, the in vivo mode of action was inferred through this analysis.

Animals↗
PubMed1986

Intra-arterial chemotherapy with ACNU for the treatment of glioblastoma. Preliminary experience.

In November 1985, we started a study of intra-arterial (i-a) chemotherapy with ACNU for the treatment of glioblastomas of the central nervous system: 19 patients with histologically proved glioblastoma and recurrent, progressive or newly diagnosed disease were entered. Five patients were treated three times. We observed reduction of mass effect, of neovascularization, and of contrast enhancement. As to the time of survival, or follow-up is too short to allow definite conclusions. The quality of life in those patients who received several courses of chemotherapy, did not deteriorate as evidenced by a constant Karnofsky performance rating score. Systemic complications of i-a chemotherapy were negligible. However, some severe side-effects were seen: cerebral ischemia in two cases, and amaurosis in one. Direct ACNU related neurotoxicity was not seen to the present. According to these preliminary results, we feel encouraged to treat further patients with i-a chemotherapy, particularly in view of the disappointing results of several other treatment modalities in the management of glioblastomas of the brain.

Adult↗
PubMed1985

[Clinical value of postoperative chemotherapy for non-small cell lung cancer--with special reference to long-term combined chemotherapy combined with immunotherapy].

The main reason for unfavourable surgical outcome of lung cancer is latent distant metastases over looked during surgery, which ultimately cause recurrence, or death of the patients even in cases undergoing curative surgery. This fact necessitates the indispensable use of systemic adjuvant therapy in patients under going surgery for lung cancer. There have been mary reports concerning the clinical efficacy of surgical adjuvant chemotherapy for non-small cell lung cancer using various kinds of drugs in various treatment modalities, but the results have been controversial. During the past eleven years, we have used postoperative chemotherapy in three ways over three different periods: in the earliest period, short-term combined chemotherapy (STCC) was used, in the middle period, intermittent long-term combined chemotherapy (ILTCC) was used in combination with immunotherapy for a randomized group, and in the latest period, when continuous long-term combined chemotherapy (CLTCC) with immunotherapy was employed. A comparison was then made between these three kinds of treatment groups. In Comparing of the results obtained for the earliest and middle periods, ILTCC showed a significantly improved beneficial effect over STCC in terms of further increased survival rate. Furthermore, by randomized study, it was clarified that the favourable effect of ILTCC was further improved by concomitant use of immunotherapy. CLTCC with immunotherapy carried out in the latest period seemed to be prevent early recurrences in patients with stage I or II who underwent curative surgery, even though a short-term observation period of for 20 months was employed. It is conceivable that the latest treatment modality used will exerted best the most favourable beneficial effect in comparison with the two early treatments. A review of the literature was presented along with a discussion of the clinical value of chemotherapy and immunochemotherapy as a surgical adjuvant.

Adenocarcinoma↗
PubMed1985

[A randomized trial of 3-drug combination chemotherapy in small cell lung cancer--CPA/ACNU/VCR vs ADR/ACNU/VCR].

From April 1981 to February 1983, 116 untreated patients (ECOG PS 0-3) with histologically or cytologically proven small cell lung cancer were randomly allocated to chemotherapy regimen using CPA.ACNU.VCR (CNV, n = 64) or ADR.ACNU.VCR (ANV, n = 52). The objective tumor response was 29.7% (19/53) for the CNV regimen and 48.1% (25/48) for the ANV regimen, but there was no statistically significant difference in these groups. Median survival time was 22.9 w for the CNV regimen (n = 64) and 42.4 w for the ANV (n = 52) regimen. The survival rate was statistically significantly higher for the ANV regimen compared to that of the CNV regimen (P greater than 5%). The toxicity showed no difference between these groups. Addition of ADR to ACNU + VCR was effective, but addition of CPA to these two drugs was not effective.

Aged↗
PubMed1985

[ACNU delivery to malignant glioma tissue by osmotic blood brain barrier modification with intracarotid infusion of hyperosmoral mannitol].

Drug delivery to the tumor has been one of the major subjects in the field of brain tumor chemotherapy because of blood brain barrier. Recent studies including quantitative autoradiographic studies revealed that blood brain barrier is present and intact in the brain adjacent to tumor where viable tumor cells are infiltrating, and also in the tumors which are early in the development. In 1972 Rapoport et al demonstrated that it is possible to transiently and reversibly open the blood brain barrier by an intracarotid infusion of a hyperosmoral solution. This technique is found to increase cerebrovascular permeability to chemotherapeutic agents. Six cases of glioma, including 4 astrocytoma grade 4, 1 astrocytoma grade 3, 1 astrocytoma grade 2, were treated during operation with intracarotid infusion of ACNU 100 mg/body/5 min. (1.3-2.2 mg/kg) following intracarotid infusion of 20% mannitol 200 ml (1.3-1.6 ml/sec) through the catheter in the internal carotid artery set preoperatively, and ACNU concentration in tumor tissues and blood were measured at 5, 10, 15, 20, 25, 30, 40, 60 minutes after that. On every case mannitol contrast enhancement CT was studied by the intracarotid infusion of 60% conray 100 ml/5 min. following the intracarotid infusion of 20% mannitol 200 ml comparing with contrast enhancement CT and plain CT. Maximum ACNU concentrations in blood were 2.12-4.12 micrograms/ml (mean 3.1 +/- 0.74) at 5 min. after the intraarterial administration of mannitol and ACNU on every case. At 20 min. following the administration ACNU levels were decreased to half level (mean 1.49 +/- 0.42 microgram/ml) and 0.58 +/- 0.18 microgram/ml at 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗