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PubMed1991

[In vitro effect of combined use of BH-AC and nitrosourea derivatives against adriamycin-resistant human leukemia cell line].

Cytocidal effects of combined use of BH-AC and nitrosourea derivatives (MCNU, and ACNU) were evaluated in vitro against adriamycin-resistant human leukemia cell line (K-562/ADR-I). K-562/ADR-I cells were resistant to six kinds of agents (vindesine, mitoxantrone, aclacinomycin, cisplatin, MCNU, and BH-AC) of 14 agents tested and this cell line proved to be a multi-drug resistant line. Combined use of BH-AC and MCNU did not achieve additive effects on K-562, parent cell line and BH-AC and MCNU were less effective to K-562/ADR-I by single use. However, combination of BH-AC and MCNU showed additive effects. These results supported the evidence that combination of BH-AC with MCNU was effective in patients with multi-drug resistant malignant lymphomas.

Antineoplastic Agents↗
PubMed1991

[In vitro chemosensitivity test with several antitumor agents against eight malignant brain tumor cell-lines].

We performed an in vitro chemosensitivity test with 8 malignant brain tumor cell lines, which were established in our Department. It was shown that ACNU was moderately tumoricidal against only one cell (ONS-86) line. IFN-beta (interferon-beta) was more active against 4 cell (ONS-6, -20, -76, and -81) lines. VCR (vincristine), MTX (methotrexate), and Ara-C (cytosine arabinoside) and FK 973 were most effective against all 8 cell lines. There were some difference in the drug sensitivities among the tumors with the same pathological diagnosis. Since IFN-beta was tumoricidal against to the cells, co-culture of IFN-beta and one of other antitumor agents seemed to induce more antitumor effects. With regard to the side effects of IFN-beta, the combined therapy with IFN-beta and other drugs induced more antitumor effects against malignant brain tumor cells and seemed to reduce the side effects.

Antineoplastic Agents↗
PubMed1991

[A case of rectal carcinoma disappeared by the preoperative radiation].

A 64-year-old man was admitted to our department with a diagnosis of rectal carcinoma. Preoperative histological diagnosis was highly differentiated adenocarcinoma of Dukes' A classification (Rb', Is', 20-25 mm in diameter, PM'). Preoperative radiation (2.5 Gray/time, total 30 Gray) and chemotherapy (PSK 3g/day x 3 weeks, ACNU 30 mg/m2/week x 3 weeks) were performed on this lesion. After these therapies, form of the tumor changed to IIa', SM', which was recognized by endo-scopic examination with rectal echography. A reduction of the size was 25%. Low anterior resection, curative operation, was performed 2 weeks after the therapy. The resected rectum was examined in detail, resulting in complete disappearance of the carcinoma cell and the tumor was replaced by the inflammatory cells, fibroblasts and granular cells. These findings were compatible with grade IVB of Ohboshi-Simosatos' classification.

Adenocarcinoma↗
PubMed1990

[The changes of cerebral blood flow and metabolism of normal brain tissue after surgery, radiation, and chemotherapy in brain tumor patients: evaluated by position emission tomography].

The changes of cerebral blood flow (CBF) and metabolism of normal brain tissue after surgery, radiation, and chemotherapy in brain tumor patients were measured by positron emission tomography (PET). The subjects consisted of 6 men and 3 women, and were from 11 to 62 years old. Those were four patients with glioblastomas, one patient with malignant oligodendroglioma, one patient with astrocytoma grade II, one patient with astrocytoma grade III, one patient with pontine glioma, one patient with pineal germinoma. Seven patients were operated and pathohistologically diagnosed. Two patients with pineal germinoma and pontine glioma were not operated and radiologically diagnosed. Of 7 operated patients, first PET was performed before operation in 3 patients, and from 10 to 16 days after operation in 4 patients. Following first PET, the patients were treated with irradiation (1 case), or with both irradiation and chemotherapy (8 cases). The total radiation dose for tumor was from 59 to 61 Gy distributed in a period of 6-8 weeks. Whole brain irradiation was performed up to 30 or 40 Gy, with a remaining dosimetry (20-30 Gy focused on the tumor field. Chemotherapy consisted of intravenous administration of ACNU and oral administration of FT-207. Second PET was performed 1 month after therapy (9 cases), and third PET was performed from 4 to 24 months after therapy (6 cases). Fourth PET was performed in 2 patients (22 and 35 months after therapy), and fifth PET was performed in one patient (35 months after therapy).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

[Chemotherapy with ACNU and radiation therapy in malignant glioma in cerebral hemisphere of adult].

54 cases of malignant gliomas in adults localized in cerebral hemisphere including the location of basal ganglia and corpus callosum in 26% were survived over one month and followed more than 2 years after operation for 10 years recently. Histologically they had 40 cases of glioblastoma multiforme and 14 cases of anaplastic astrocytoma. All malignant gliomas were given an operation and radiation, classifying 4 groups due to chemotherapeutic methods; Group I (20 cases) was treated by intraarterial infusion of ACNU with 20% mannitol. The others were Group II (8 cases) treated by intraarterial infusion of ACNU only, Group III (13 cases) by intravenous infusion of ACNU only and Group IV (13 cases) by no chemotherapy. Post-operative survival rates in the malignant gliomas of Group I were that 1 year survival rate was in 16 out of 20 cases (80%), 2 years in 55%, and 5 years in 25%. In glioblastoma multiforme, 1 year survival rate of Group I was recognized in 70% and 2 years in 36%, a little better than the other treatments. 2 year survival rate of other treatments demonstrated 17% in Group II, 25% in Group III, and 11% in Group IV. CT findings of glioblastoma multiforme in Group I showed no rest tumor in 4 cases and one case of CR, and 3 cases of PR in the follow up study of 10 cases with rest tumor on CT after operation. There were no permanent complications except for temporary mild neurological deficit in 7% of Group I improving within 2 to 3 days after intraarterial infusion of ACNU and 20% mannitol. It is suggested that chemotherapy of Group I by intraarterial infusion of ACNU and 20% mannitol demonstrated a little better therapeutic efficacy than the other Groups, at least within 2 years after operation.

Adult↗
PubMed1990

[Application of DNA interstrand cross-link assay to estimate the sensitivity of tumor cells to alkylating agents].

Fluorometric method was modified and used to detect DNA interstrand crosslinks (ISC) in tumor cells after treatment with cisplatin. Linear dose-response curve was obtained. The difference of DNA ISC formation between HeLa S3 (containing O6-methylguanine methyltransferase, Mer+) and HeLa MR (devoid of O6-methyguanine methyltransferase, Mer-) cells was studied after treatment with alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). The survival fraction was also observed in Mer+ and Mer- cells treated with ACNU. It seems that DNA ISC formation may be used as one of the possible criteria in estimating the sensitivity of tumor cells to bifunctional alkylating agent and forecasting the efficacy of tumor chemotherapy.

Cisplatin↗
PubMed1990

[Combined postoperative radiotherapy and chemotherapy for malignant gliomas].

A retrospective analysis was performed on 70 patients with malignant supratentrial astrocytic gliomas (astrocytoma Grade III or glioblastoma multiforme) treated with radiotherapy combined with vincristine (VCR), ACNU and PS-K. From January 1979 through December 1983, 27 patients were treated with treatment protocol A (group A). Protocol A was as follows: (1) total dose of 50 to 65 Gy radiation was given after surgery; (2) radiation plus combination VCR (0.02 mg/kg IV on 1st and 29th day of radiation) and ACNU (2 mg/kg IV 24 hrs after VCR) (3) after synchronized radiotherapy, ACNU (2 mg/kg IV every 6 or 8 weeks) and PS-K (3 or 6 g PO every day). Other 43 patients were treated with treatment protocol B (group B) from January 1984 through June 1988. Protocol B was as follows: (1) radiation dose was same as protocol A; (2) radiation plus combination VCR (0.02 mg/kg IV one day before radiotherapy) and ACNU (2 mg/kg IV on 1st and 1 mg/kg IV on 7, 21, 35th day, 1 hour before radiotherapy) (3) maintenance chemotherapy was same as protocol A. The difference between protocol A and protocol B was based on treatment schedule of ACNU. The characteristics of all patients were studied and identified, mainly age, histologic type, initial performance status, extent of tumor resection, maintenance chemotherapy. The reduction rate of tumor volume was 46.7% in the A group and 49.9% in the B group (not significant). The survival rates at 1, 2 and 3 years after surgery were 74.1%, 55.6% and 51.9% respectively for A group, and 80.5%, 42.4%, and 42.4%, respectively for B group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

[Management results of primary intracranial malignant lymphoma].

Nineteen cases of primary malignant lymphoma of the central nervous system were reported. The clinical characteristics, diagnostic procedure and therapeutic method, especially concerning chemotherapy, were analysed. The following conclusions were obtained: 1) histological classifications and surgical procedures were not factors involved in prognosis. 2) radiotherapy was regarded as an effective but a palliative treatment. 3) combined chemotherapy for systemic malignant lymphoma, such as VEMP, VEP, COPP, seemed to be of little use for intracranial malignant lymphoma. 4) intra-arterial administration of high-dose methotrexate, ACNU and intravenous administration of high-dose cytosine arabinoside can be expected to be a useful chemotherapeutic approach.

Adolescent↗
PubMed1990

[Chemosensitivity assays for malignant gliomas].

Chemosensitivity assays including colony forming assay (CFA), MTT dye reduction assay (MTT assay) and thymidine incorporation assay (TIA) for cultured rat and human glioma cells were conducted to determine the correlation among them and the in vivo antitumor efficacy of anticancer drugs using rats implanted glioma cells. Cytotoxicity of various agents such as ACNU, ACR, CDDP, VCR or BLM, was estimated from the concentrations which caused 50% inhibition of the cell growth at the peak plasma concentration. The survival time of tumor bearing rats was assessed after ip treatment with these agents at their estimated clinical doses. This parameter was greater in the drugs that were shown to be highly sensitive in CFA and was consistent with the data for CFA. In the chemosensitivity assays, CFA closely correlated to MTT assay for all agents except VCR, but poorly so to TIA. The results in this study indicate that MTT assay seemed to be useful for determining the chemosensitivity of anticancer drugs and that chemosensitivity assay should be conducted depending on the nature of anticancer drug.

Animals↗
PubMed1990

[Radiation injury of the normal brain tissue after external radiotherapy of brain tumor].

The calculated dose expressed by neuNSD (or neuret) shows a significant relationship between a therapeutic dose and a post-radiation time in the normal brain injury. An aged patient and a patient with the vulnerable brain in the irradiated field had the high risk of radiation injury. Radiotherapy needs to consider the cost-benefit balance for those risk patients. The hyalinization of the vessels and demyelination were observed even in low-dose radiation areas in non-aged patients, and in aged patients fibrinoid necrosis was observed in low-dose radiation areas. The combination of intraarterial chemotherapy and radiotherapy increased the injury of the brain. If the low-density area existed within the irradiated field on CT, it could be a cause of radiation injury. Steroid and anticoagulant drugs should be given to recover from the condition before radionecrosis.

Aged↗
PubMed1990

[Successful bronchial arterial infusion (BAI) of ACNU in the treatment of pulmonary infiltration of acute non-lymphocytic leukemia (ANLL) cells].

A 35-year-old man was admitted to our hospital because of lumbago on March 25, 1988. On admission white blood count was 1,200/microliters with neutrophils of 9% and lymphocytes of 91%, hemoglobin level was 11.2g/dl and platelet count was 55 x 10(3)/microliters. Bone marrow smear showed 77% leukemic cell including non-specific or specific esterase-positive cells. Chest X-rays showed the presence of mediastinal tumor and diffuse reticular shadows. A diagnosis of ANLL was made and a hematological remission was obtained after one course of combination chemotherapy consisting of BH-AC, daunorubicin and prednisolone, but the enlarged mediastinal tumor and pulmonary infiltration worsened rapidly followed by marked dyspnea. This radiographic abnormal shadow was confirmed to be leukemic infiltration from the finding of transbronchial lung biopsy. We hesitated to give systemic chemotherapy because he also had had liver abscess. Accordingly we performed BAI of ACNU at a dosage of 150 mg which led to a dramatic improvement in dyspnea. 60Co therapy was performed on the mediastinal tumor. On May 30, when he had a relapse, he was unsuccessfully treated with systemic chemotherapy. The leukemic cells invaded most of the organs and the patient died on July 19, 1988. It is likely that BAI of ACNU for leukemic pulmonary infiltration was effective.

Adult↗
PubMed1990

[Immunohistochemical study of placental form of glutathione S-transferase in human brain tumors and fetal brains].

The activity of glutathione S-transferase placental form (GST-pi) was examined in 100 cases including various histologic subtypes and grading of human brain tumors and 10 cases of fetal brains by immunohistochemical studies. The 69% of cases with brain tumors were shown to be positive for GST-pi. This activity in neuroepithelial tumors tended to increase in order to tumor grading, however, medulloblastoma and primitive neuroectodermal tumor (PNET) were not immunoreactive with GST-pi. Embryonal carcinoma showed strong staining, although fetal brains were negative. The metastatic brain tumors showed the same reactivity with GST-pi as those of original carcinomas. Moreover, the difference of GST-pi activity was investigated on some brain tumors treated with or without antitumor drug, such as 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). The 85% of recurrent cases showed strong staining with GST-pi, and GST-pi activity seemed to be increased after treated with ACNU. The present study indicated that GST-pi might be a useful marker for human brain tumor, as the same conclusion was applicable to other neoplastic lesions examined previously. It is suggested that the increased GST-pi activity with malignancy of tumor may indicate the tendency to recurrence. The presence of such activity in tumor cells may also imply their acquired multidrug resistance. Our findings suggest that the evaluation of GST-pi activity in brain tumors will offer a predictive value for eventual behavior of the tumor.

Biomarkers, Tumor↗
PubMed1990

[Chemotherapy responsiveness of brain tumors in subrenal capsule assay].

The 6-day subrenal capsule assay for determining chemotherapeutic sensitivities of brain tumors was studied. Rat glioma 9L and ACNU resistant 9L-2 were transplanted under the renal capsule of normal immunocompetent WKA rats for laboratory investigation. Evaluation of implanted tumor growth till 12 days was performed. The effects of chemotherapeutic agents administered intravenously were evaluated by measuring the growth rate of implanted tumor specimens. The results obtained from SRC were compared with the results from colony forming assay. Both were correlated to each other. On the other hand, histological investigation revealed that implanted human tumor cells had been diminished and implanted tumor was replaced by immunoreactive cells from the host in many cases. These results threw doubt on a reliability of SRC. To avoid this immunoreaction, cyclophosphamide was injected as immunosuppressive agent subcutaneously 24 hours before implantation. In such cases, the growth rates of implanted tumors were increased and histologically the implanted tumor cells existed for 6 days after implantation. Twenty-three malignant brain tumors (malignant astrocytomas 16, metastatic tumors 5, malignant lymphoma 2) were obtained as surgical specimens. Evaluable assay rate of our study were 89%. 15 patients with malignant astrocytomas were studied about correlation between the sensitivities of ACNU and post-operative clinical courses. Overall clinical correlation of 15 cases of malignant astrocytomas was 47%. These results from subrenal capsule assay are not seemed to be beneficial for clinical use. Immunoreactive response when using immunocompetent rats must be solved in future.

Animals↗
PubMed1990

Neurotoxicity and pharmacokinetics of intrathecal perfusion of ACNU in dogs.

To test the feasibility of intrathecal perfusion of ACNU (3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitro sou rea hydrochloride) in the treatment of subarachnoid dissemination of malignant glioma, the neurotoxicity and pharmacokinetics of ACNU were studied in dogs. ACNU [1-2 mg dissolved in 10-20 ml of lactated Ringer's solution or artificial cerebrospinal fluid (CSF)] was administered via the right lateral ventricle by constant drip infusion and CSF was drained by lumbar puncture. The infusion time was from 15 to 71 min. For the control, a bolus injection was given. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord revealed only mild denudation of ependyma in the wall of the ventricles in a dog treated three times with 2 mg ACNU (perfusion twice, bolus injection once) and in 2 dogs perfused with 1 mg ACNU once a week for 10 weeks. ACNU was not detected in lumbar CSF after bolus injection into the lateral ventricle. When 1 mg of ACNU, dissolved in 10 ml of artificial CSF, was perfused for a duration of 22 to 31 min, it started to appear in the lumbar CSF 10 to 15 min after the start of perfusion, reaching a maximum concentration of 13.88 to 22.31 micrograms/ml. The area under the drug concentration-time curve was 344 to 706 micrograms x min/ml; the half-time was 15.5 to 19.5 min. The distribution volume was 30.6 to 54.1 ml. These findings suggest the feasibility of intrathecal perfusion of ACNU in the treatment of patients with subarachnoid dissemination of glioma.

Animals↗
PubMed1990

[Application of interleukin 1 in the treatment of malignant gliomas with special reference to the experimental combination therapy with ACNU].

The therapeutic potential of interleukin 1 (IL-1) in the treatment of malignant glioma was investigated. The direct effect of recombinant human IL-1 beta (rHuIL-1 beta) on cultured U-373 MG glioma cell was evaluated in vitro by BrdU uptake assay, and these effects were compared with those of human interferon beta (HuIFN-beta). Though a growth inhibition and an increase of the percentage of process bearing cells were observed with rHuIL-1 beta at a concentration of 100 ng/ml, these in vitro effects of rHuIL-1 beta were less than those of HuIFN-beta at the same concentrations. Prevention of and enhanced recovery from myelosuppression caused by ACNU by rHuIL-1 beta were evaluated in BALB/c mice. Intravenous injection of ACNU at a dose of 60 mg/kg caused marked decreases in the number of leukocytes, neutrophils, reticulocytes and thrombocytes after seven days. Pretreatment with 1 microgram/mouse of rHuIL-1 beta as a single i.p. injection had a significant preventive effect on these myelosuppression including thrombocytopenia. Enhanced recovery by rHuIL-1 beta administrated seven days after injection of ACNU was also observed. Experimental combination immunochemotherapy with ACNU and rHuIL-1 beta was performed in nude mice inoculated with human glioblastoma subcutaneously. More than 60 mg/kg of ACNU given intraperitoneally inhibited the growth of human glioblastoma in nude mice, but had no effect on survival time of nude mice. The antitumor effect of ACNU was significantly augmented by coadministration of 1 microgram/mouse rHuIL-1 beta. The elongation of the survival time of the tumor bearing nude mice was also observed in combined use of ACNU with rHuIL-1 beta. These results suggest that the combined use of IL-1 with chemotherapeutic agents seems to be desirable for clinical application in the treatment of patient with malignant gliomas from the viewpoints of the direct anti-tumor effect, the enhancement of the host immunity, and the prevention of myelosuppression caused by those agents.

Animals↗
PubMed1990

[Interstitial hyperthermia of malignant brain tumors using implant heating system (IHS)].

We have developed an implant heating system (IHS) for interstitial hyperthermia of brain tumors. IHS consists of three compartments: ferromagnetic implant with low Curie point, induction coil and generator to produce high frequency magnetic field. The device works as follows: It is heated up to a Curie temperature (Tc) by Eddy current under the magnetic field. Heat generated in the implant is conducted to the tumor tissue into which it has been implanted. To evaluate the effect of this hyperthermia, a brain tumor model was produced by innoculation of VX2 tumor cells and treated either by hyperthermia with IHS alone, chemotherapy with ACNU alone, or with a combination of both. The longest survival was obtained by the combined treatment, and significant prolongation of survival was found in the single treatment groups. In the Phase I clinical trial, one or several implants (1.8 mm X 15 mm, Tc = 68 degrees C) made of Fe-Pt alloy were placed in the tumor by CT guided stereotactic procedure, or manually during craniotomy. Hyperthermia of above 42 degrees C for 30 to 60 minutes twice a week was brought about in ten cases of malignant brain tumor. CT evaluation was made in nine cases treated for more than ten times in this way. Five out of the nine cases responded to this hyperthermia with irradiation. In conclusion, a safe, repeated and longterm treatment was possible without significant side effects. The hyperthermia with IHS may also be applicable to benign intracranial tumors and neoplasms in other part of body as well.

Adult↗
PubMed1985

[Antineoplastic effect of Hu-IFN-beta and other anticancer drugs on malignant brain tumors in athymic nude mice].

We have been studying the therapeutic effect of anticancer drugs such as ACNU and vincristine in human glioma-bearing nude mice models and this time, the effect of interferon was also evaluated. Since 1980, the phase 1, 2 clinical trials on Hu-Interferon (IFN) have been studied in the neurosurgical field and the effect is now regarded to be not as pronounced as previously expected. It is difficult to compare the effect of IFN with other anticancer drugs in an in-vivo study, because of the species specificity of IFN, and only a few studies have so far been reported. With respect to evaluating the therapeutic effect of IFN, the nude mouse model is thought to be useful. The anticancer activity of beta-IFN in nude mice, receiving subcutaneous transplants of human brain tumors (6 strains) was compared with that of conventional anticancer drugs. After 3 weeks of treatment with ACNU, vincristine, bleomycin, mitomycin C, alpha-IFN, beta-IFN, poly ICLC, the tumor reduction rates were evaluated by Battelle's method. Although in 2 out of 6 glioma strains, the tumor reduction rate (treated/control values) treated with beta-IFN was evaluated as effective, the effectiveness of beta-IFN was inferior to that of ACNU and vincristine. Therefore, further studies are indicated to evaluate the efficiency of the drug at higher dosage levels and to determine its tolerance dose. The combined modality treatment such as chemotherapy and radiation are issues that are still to be settled by further studies.

Animals↗
PubMed1985

[Diagnosis and treatment of malignant melanoma].

Malignant melanoma is one of the most malignant froms of cancer, for which the prognosis is still very grave. However, it need not necessarily be regarded as such a fearful tumor if it is found at an early stage and treated thoroughly and adequately. An understanding of the early clinical changes in the size, color and shape of the tumor is required, and early discovery can save a patient's life. Histopathological examination should be done for diagnosis, and S-100 protein should be checked together with monoclonal antibody studies sometimes. The main principle of treatment in the early stage of malignant melanoma is to make an incision 2 to 5 cm away from the edge of the tumor. As a rule, exploratory excision and minor resection should not be performed. It may be said, accordingly, that multidisciplinary treatment should only be given for malignant melanoma of stage 1b and more advanced stages. At present, chemotherapeutic combinations used as the first choice in Japan are two regimens, one of which is DAV (DTIC, ACNU and vincristine), and the other, PAV (peplomycin, ACNU and vincristine). The effectiveness rate with DAV and PAV have been approximately 30% in various clinical studies. Favorable clinical responses obtained by radiotherapy have often been observed after fast neutron irradiation and hyperthermia therapy. Immunotherapy and interferon treatment are also often applied for malignant melanoma.

Antineoplastic Combined Chemotherapy Protocols↗