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PubMed1983

[Second-look operations and chemotherapy for malignant tumors of the brain].

Second-look operations for glioblastomas, one of the most malignant types of brain tumor, were performed after the administration of chemotherapeutic treatments of general-VM 26 plus ACNU, local-MTX, or interferon-beta in each of ten, two, and three cases, respectively. Patients who had received the treatments were divided into two groups, living and deceased, as of August 1982. Therapeutic evaluation was performed with clinical parameters. Among the cases of CR, one (a 14-year-old female) had undergone surgery four times in the four years following onset, and no trace of tumor shadow appeared on the CT grams that were taken one month after the last surgery. Her performance was evaluated as almost 100% (ECOG). In cases of local administration, one case, which had been treated with IFN-beta, demonstrated an apparent decrease in the growth fraction and a pronounced decrease in tumor progression potency. Cell kinetic analyses were also performed, and cell cycle time and growth fraction were estimated by computer with the aid of flow cytometry. Efficacious chemotherapy yielded a decreased value of the growth fraction and an increase in cell cycle time. The decreased value of the growth fraction demonstrates especially well the effectiveness of a chemotherapeutic regimen. The cell kinetic analyses aided in the rational establishment of a chemotherapeutic regimen. Second-look operations for malignant brain tumors will enable more effective refinements in chemotherapeutic regimens and more successful results.

Adolescent↗
PubMed1984

[Case of metastatic malignant melanoma responded to combination chemotherapy with DTIC].

A 60-year old woman with metastatic malignant melanoma who was well responded to a combination chemotherapy including DTIC was reported. She was noted a lentigo in the left first toe and histological examination revealed malignant melanoma in October 1978. Amputation of the left lower leg and dissection of the left inguinal lymph nodes had been done. OK-432 was injected as postoperative immunotherapy. She was readmitted to our hospital with the symptoms of pain and numbness of the left arm. Physical examination revealed a palpable mass in the left supraclavicular region. Incisional biopsy of the supraclavicular mass revealed metastatic malignant melanoma. She received a combination of 100mg DTIC i.v. for 5 days, 100 mg ACNU i.v. for one day and 1 mg VCR i.v. for one day (DAV chemotherapy) postoperatively. Subcutaneous injection of OK-432 with the dose of 5 KE per week was continued. Major side effects of DAV chemotherapy were nausea and transient leukocytopenia. No serious side effects were observed. On completion of the first course of DAV chemotherapy, abnormal shadow of the left apex was completely disappeared and on completion of the third course of DAV chemotherapy, high density area was markedly decreased in the cervical CT. She gained symptomatic reliefs and was discharged in August 1983. The combination chemotherapy including DTIC appeared to be effective in the treatment of metastatic malignant melanoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

[Meningeal gliomatosis models as a chemosensitivity assay system].

Experimental models of meningeal gliomatosis (MG) have been produced by intracisternal inoculation of C6 and 9L glioma cells into Wistar and Fisher 344 rats, respectively. Chemotherapy of these models and in vitro chemosensitivity assay for these cell lines were studied with ACNU, BCNU and VM-26. In vitro chemosensitivity assay revealed that 9L cells were sensitive to all of the anticancer drugs above, and that C6 cells were resistant to ACNU and BCNU, but not to VM-26. In vivo experiment, the survival time of the rats inoculated with 9L glioma cells (9LMG) was prolonged by both ACNU and BCNU but not by VM-26. None of these drugs were effective against the rats inoculated with C6 glioma cells (C6MG). It is concluded that the result of in vitro chemosensitivity assay is not always correlative with that of in vivo. This implies that an in vivo chemosensitivity assay system including MG models is indispensable in researching into chemotherapy of brain tumor.

Animals↗
PubMed1984

[Enhanced effect of reserpine on growth-inhibitory action of ACNU on ACNU resistance C6 glioma].

Reserpine was found to enhance the effect of ACNU on ACNU-resistant C6 glioma (C6/ACNU). When reserpine was added to the culture medium at the concentration of 10 microM, the IC50 of ACNU for C6/ACNU was decreased to the level of that for C6. Intracellular uptake of ACNU increased in both resistant and sensitive cells when 10 microM reserpine was added to the culture medium. This phenomenon is more remarkable in C6/ACNU than in C6.

Animals↗
PubMed1984

[A case of refractory acute lymphocytic leukemia who achieved a complete remission by mitoxantrone].

A 21-year-old male was diagnosed as having acute lymphocytic leukemia in March 1982. The patient was immediately treated with VENP [vincristine (VCR), Endoxan (EX), Natulan, prednisolone (Pred)] therapy, yielding a partial remission. After one course of AAAP [ACNU, adriamycin (ADM), methotrexate (MTX), Pred] therapy, a combination chemotherapy with behenoyl-arabinocytosine, daunomycin (DM), vindesine and Pred was administered, which produced a complete remission lasting for 52 days. For the relapse, L-Asparaginase (L-Asp) and Pred therapy, large doses of MTX, the combination chemotherapy with VCR, EX, L-Asp and Pred and VEMP (VCR, EX, 6-MP, Pred) therapy were administered consecutively, PR was maintained but CR was not achieved. While receiving the combination chemotherapy consisting of VCR, EX, carbocone and Pred, the leukemic cells of his bone marrow increased gradually and reached to 70%; at that time cumulative doses of DM and ADM reached to 360 mg and 120 mg respectively. Thereafter mitoxantrone (MX) was administered on a 5-day iv schedule using daily dose of 4 mg/m2. Leukopenia was prolonged and liver dysfunction appeared, and they were recovered gradually. Two additional courses of MX using the same schedule and daily dose were given combined with Pred. Prolonged leukopenia and transitional liver dysfunction were also observed. He attained a CR, which was of short duration. It was clinically indicated that MX did not have a complete cross-resistance with many antileukemic agents including DM and ADM.

Adult↗
PubMed1983

[ACNU delivery to malignant tumor tissue and serum--route of administration and combined use of phenobarbital].

Since nitrosourea compounds as chemotherapeutic agent can cross the blood brain barrier, they are widely used in the treatment of malignant brain tumors. ACNU (3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride) has become a popular agent, as it is water-soluble and has shown potent effectiveness for treating gliomas. Only a few studies have ever been reported concerning the pharmacokinetics of ACNU in human brain tumors. Intra-arterial administration of chemotherapeutic agents has recently been paid special attention, because it is expected to be more effective than intravenous administration. On the other hand, phenobarbital as an anticonvulsant, widely used in clinical management of malignant brain tumor patients has been reported to reduce the toxicity of nitrosourea compounds by induction of hepatic microsomal enzyme relating to their metabolism. In this report, malignant brain tumor patients were divided into two groups; ACNU was administered either by internal carotid or intravenous route. ACNU concentrations in blood or tumor tissue following the administration were serially compared between these two groups. Patients were also divided into another two groups; ACNU was administered in combination with or without phenobarbital. Between these two groups, ACNU in concentrations in blood were serially compared in order to detect the influence of phenobarbital. ACNU concentrations in tumor tissues were measured at 5, 10, 15, 20, 25, 30, (40, 45, 50), 60 minutes after intravenous (IV) or internal carotid arterial (ICA) administration of ACNU (2-3 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1983

[Evaluation of radiation immunochemotherapy in the treatment of malignant glioma. Combined use of ACNU, VCR and PS-K].

In a follow up study of 38 patients with supratentrial malignant glioma verified histologically during the 3 years from 1979 to 1982, the same therapeutic method which was the postoperative synchronized radiation-immunochemotherapy was applied. And we investigated the relationships between the survival rate and the histological malignancy, the operative area, and age of admission. Total dose of 5000 to 6000 rad radiation was given after surgery. 0.02 mg/kg of VCR was administered intravenously on the first and the 29th day of radiation, and 2 mg/kg of ACNU was administered intravenously 24 hours after VCR administration. After synchronized radiotherapy, 2 mg/kg of ACNU was given every 6 weeks and 3 g of PS-K was given orally every day. Dose of PS-K was increased especially during the radiation and for 2 weeks after ACNU administration. This radioimmunochemotherapy was applied to 38 patients with malignant glioma, 25 cases of glioblastoma multiforme, 12 cases of malignant astrocytoma, one cases of malignant ependymoma, one case of malignant oligodendroglioma. A complete clinical course of all patients was observed. 18 of 38 cases are surviving. The survival rate of malignant gliomas was 71.2% for one year, 47.6% for 2 years, 34.8% for 3 years. The survival rate of glioblastoma was 56.3% for one year, 36.9% for 2 years, 12.3% for 3 years. The survival rate of the patients receiving macroscopically total removal was higher than that of the patients receiving subtotal removal. The survival rate of the younger patients (under 49 years old) was higher than that of the older patients (over 50 years old). Side effect of this therapy was myelosupression in 75.8%.

Adjuvants, Immunologic↗
PubMed1984

[Chemotherapy for experimental subarachnoid dissemination model of brain tumor].

Chemotherapy was applied for experimental subarachnoid dissemination model of brain tumor which was established in male Wister-SPF (SLC) rats inoculated intracisternally with 2 X 10(5) C6 rat glioma cells. Nontreated animals died about 24 days after inoculation. Autopsy findings of the animals showed localized or multifocal invasion of the tumor on leptomeninges in cisterna magna, and partially infiltration into the parenchyma of the cerebellum and medulla oblongata. Three days after inoculation, the tumor deposition and proliferation already occurred. Several tumor cell layers were found in the subarachnoid space over the cerebellomedullary surface. Tumor bearing animals were at first treated by single agent. These are ACNU administered intraperitoneally, methotrexate administered intracisternally, and OK-432 administered intraperitoneally. In the next stage, combination of these drugs was applied. ACNU, 3 mg/kg i. p., on Day 3, was effective in elongation of median survival time by 23.6%, statistically significant (P less than 0.02). Methotrexate, 0.25 mg/kg i.th., on Day 3, was also effective in elongation of median survival time by 8.4%, statistically significant (P less than 0.05). OK-432, 0.1 KE/kg i. p., daily, 14 times, from Day 3 to Day 16, was ineffective in elongation of median survival time. Combination of ACNU, methotrexate and OK-432, in the same schedule as described above, produced the longest median survival time of 42.4%, statistically significant (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

[MCNU effectiveness on brain tumor. Part I: Antitumor activity in vitro on human glioma and neuroblastoma cell lines].

A new water-soluble nitrosourea ( MCNU ) was tested for its antitumor activity against fourteen human glioma cell lines and two neuroblastoma cell lines. Four experiments were performed to determine its antitumor activity: inhibition of cell growth, comparison with ACNU, morphological observation, and analysis of DNA histogram with flowcytometry . Seven out of 14 gliomas (50%) and one neuroblastoma cell lines showed more than 50% inhibition of cell growth in vitro, appearance of giant multinucleated cell morphologically, and DNA accumulation in G2+M and/or S phase of cell cycle in the medium of 10 micrograms/ml MCNU . Antitumor activity and spectrum of MCNU against human brain tumors were almost the same as with ACNU.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

[Local blood flow and capillary permeability in the experimental meningeal carcinomatosis].

Local blood flow and capillary permeability of the rats with meningeal carcinomatosis were studied with macroautoradiography, and relationship between blood flow, permeability and effects of chemotherapy is discussed. Experimental meningeal carcinomatosis was induced in the Wistar rats by inoculating Walker 256 tumor into cisterna magna. One to 12 days after inoculation, rats were used for measurements of blood flow (by 14C- iodoantipyrine) and capillary permeability (by 14C-alpha-aminoisobutyric acid). Images of autoradiography and corresponding histological appearances were analyzed. In the early stage of tumor growth (2 to 3 days after inoculation), a few layers of tumor cells were identified in the ambient cistern. Blood flow in the vicinity of the tumor cell layer was noted, but no increase in capillary permeability was found. In the middle stage of tumor growth (3 to 5 days after inoculation), 10 to 20 layers of the tumor cell was noted in the ambient cistern. Blood flow in the tumor was evident and capillary permeability began to increase. In the late stage of tumor growth (6 to 12 days after inoculation), a mass of the tumor cells was noted in the ambient cistern. In this stage, blood flow in the tumor was similar to that of cerebral gray matter and capillary permeability increased markedly. Brain adjacent to the tumor also showed increase in capillary permeability. The result correlated well to the previous result of experimental chemotherapy. Form those data, lipid soluble drugs which cross blood-brain barrier readily are recommended for the early stage of meningeal carcinomatosis, and water soluble drugs which has limitations to cross blood-brain barrier can not be recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

[Synchronization chemoradiotherapy for malignant gliomas].

Cellular synchronization chemoradiotherapy was performed in 122 patients with glioblastoma and malignant astrocytoma (GrIII) registered between April 1977 and August 1982. The study was a non-randomized clinical phase II trial. The chemotherapeutic agents employed as synchronizers during the irradiation were VM26 (epipodophyllotoxin) and vincristine (VCR) as plant alkaloids and ACNU as a nitrosourea. Either VM26 or VCR was administered on D1, D2 and D3 at the dosage of 1 mg/kg (0.025 mg/kg-VCR) body weight. ACNU was administered on D2 and D3 at the dosage of 1 mg/kg body weight. The duration of the chemotherapy was eight to fourteen days at the initial induction stage and almost eight weeks at the maintenance stage. Thus, two synchronization arms of VM26 + ACNU and VCR + ACNU were employed. The regimen-VM 26 + ACNU + Radiation (Rad) could yield the initial induction of CR + PR-30%, NC-50%, and PG-15% in 58 cases. Long-term survival, calculated by the cumulative survival rate, was as follows: one year, 58%; two years, 42%; three years, 32%; four years, 30%, and five years, 25%. The regimen VCR + ACNU + Rad could yield the initial induction of CR + PR-28%, NC-49%, and PG-23% in 64 cases. The cumulative survival rate was calculated as follows: one year, 55%; two years, 42%; three years, 27%; four years, 22%, and five years, 22%. As a control, particularly for the survival rate, the data of the All-Japan Registry were revised to correspond to our study population. The survival rate of simple radiation cases thus revised was as follows: one year, 43%; two years, 23%; three years, 11%; four years, 7%, and five years, 5%. The comparison between VM 26 plus ACNU and VCR plus ACNU yielded a higher initial induction response of 35% for the former (vs. 28% for the latter), although it is difficult to make a judgement on the excellence of the regimen involving VM 26 plus ACNU, because this trial was clinical phase II. On the other hand, compared with the data from the All-Japan Registry, each regimen of cellular synchronization radiation therapy could achieve statistically more excellent responses both in the initial induction and the long-term survival (p less than 0.01). Thus, cellular synchronization radiation therapy is a hopeful therapeutic method for malignant glioma, with less side effects and statistically confirmed higher responses.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

[Flow cytometric study of enhanced effect of anti-cancer drugs induced by nicardipine hydrochloride].

Flow cytometric analysis was used to study the effect of a calcium influx blocker, nicardipine hydrochloride, on the cytotoxicity of anti-cancer drugs in tumor cells. The parameters used for this study were DNA- and protein-cell distribution histograms. Cells and drugs used for this study were C6 cells from CD Fisher rat glioma and VCR, ADM and ACNU, respectively. The growth inhibitory effect estimated by concentration at ID50 on C6 cells was indicated as follows; VCR showed an 89-fold enhancement, while ACNU showed little enhancement following addition of nicardipine hydrochloride. DNA and protein histograms obtained by flow cytometry revealed almost the same effects as cells which were studied using high concentration of VCR without nicardipine hydrochloride. For the other drugs, ADM showed a small enhancement on histograms, while with ACNU, little enhancement was noted as well as the inhibitory effect of each drug described above. The results indicate that nicardipine hydrochloride greatly affects the cell cytotoxicity of VCR but not so much with ADM and ACNU. From these results, it appears that this drug enhances the action of anti-cancer drugs not only by merely blocking the efflux of drugs from cells but also by other mechanisms which remain to be clarified.

Animals↗
PubMed1984

[Development of ACNU-resistant meningeal gliomatosis models: establishment of resistant rat glioma subline against ACNU].

Induction in vivo of resistance of C6 rat glioma and 9L rat glioma to ACNU [1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride] was studied and ACNU-resistant rat meningeal gliomatosis models were developed by using these resistant glioma sublines. Rapid acquisition of resistance to the agent was present at 2nd transplant generation in both glioma lines. Cellular resistance to ACNU remained unchanged in the absence of drug over 5 transplant generations in vivo in spite of the fact that the drug treatment was discontinued at the 5th generation after a complete resistance was induced. On the other hand, the degree of resistance of 9L resistant subline established by only once ACNU treatment was found to be decreased after 5 transplant generations in vitro. Degree of resistance at the cellular level was observed with each subline by in vitro technique and compared with each other. Each subline was found to have different degree of resistance: 9L resistant subline showed higher resistance than C6 resistant subline, and the differences in degree of resistance between 9L resistant subline and C6 resistant subline were approximately 750 and 20, respectively, when they were expressed as ratios of IC50 (drug concentration for 50% growth inhibition) for the resistant subline to the original one.

Animals↗
PubMed1984

[Antitumor activity of a new nitrosourea, MCNU, on a cellular morphological basis evaluated by a new in vitro antitumor sensitivity assay].

Using our new in vitro antitumor sensitivity assay, the basis of which depends on predictive analysis of morphological findings of L1210 leukemia cells under the influence of antitumor agents, 5 kinds of nitrosoureas including MCNU were comparatively tested for antitumor activity. A cell killing effect became apparent very soon under BCNU and CCNU, rather late under Methyl-CCNU and MCNU, and intermediately under ACNU. Various cellular biological effects were apparently induced in L1210 cells by MCNU and its mechanism of action seemed to be broader than that of any other members of the nitrosoureas.

Animals↗
PubMed1984

[Clinical efficacy of a quadruple combination chemotherapy with ACNU, adriamycin, methotrexate, and prednisolone for patients with non-Hodgkin's lymphoma, who were refractory to VEPA (P) treatment].

A quadruple combination chemotherapy with ACNU, adriamycin, methotrexate and prednisolone (AAAP), was performed on 9 patients with non-Hodgkin's lymphoma, who had been previously treated with a VEPA (P) regimen. Complete remission rate was 44% (4/9) and, in four other patients, the tumor was decreased in size. Complete remission duration was from 30 days to over 390 days. Median survival time was 105 days. Myelosuppressive toxicity was severe. In eight patients, WBC counts were less than 3,000/mm3. In six patients, platelet counts were less than 100,000/mm3. An AAAP regimen is useful in relapse or for resistant forms of non-Hodgkin's lymphoma.

Adult↗
PubMed1983

[Treatment of acute leukemia in relapse].

For the early diagnosis of recurrence of acute leukemia, differential count of the 5000 leukocytes was found very effective. In 29 cases out of 30 cases whose leukemic cells were elevated to the level higher than 10/5000 from the level of 0-4/5000 in stable stage of remission, overt recurrence was diagnosed by peripheral blood or bone marrow examination after 3-12 weeks. Prevention of overt recurrence was observed in several cases, in which an intensive treatment was administered at the early stage of recurrence. For the treatment of cases with overt recurrence, it is important to plan the treatment with drugs different from those used in previous treatment. AAAP therapy or new drugs such as mitoxantrone might be considered. In cases in which leukemic cells proliferate earlier than normal cells after intensive treatment, a sustained small dose Ara-C therapy was often effective.

Acute Disease↗