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PubMed1984

Antitumor activity of a nitrosourea derivative, CNUA, on murine tumors.

The antitumor activity of a new derivative of nitrosourea, 3-[3-(2-chloroethyl)-3-nitrosoureido]-3-deoxy-D-allose (CNUA), against murine tumors was studied. CNUA showed significant antitumor activity against L1210 leukemia, Lewis lung carcinoma, B-16 melanoma and autochthonous lung tumor induced by 1-ethyl-1-nitrosourea. The effect of CNUA, chlorozotocin, and ACNU on the peripheral white blood cell count (WBC) in normal CDF1 mice was examined. The lowest WBC count occurred 3 days after administration at the therapeutic dose level and the decreased value returned to the normal level 7-14 days following administration of CNUA and chlorozotocin. CNUA also exerted a depressive action on both humoral and cell-mediated immune response to sheep red blood cells determined by the serum hemagglutinin titer, plaque-forming cells in the spleen, and delayed-type hypersensitivity reaction, while the suppression was almost the same or less than that obtained with chlorozotocin when compared at the dose resulting in similar antitumor activity. These findings suggest that the antitumor activity of CNUA was not at all inferior to those of other nitrosoureas. The bone marrow toxicity was moderate and did not last long.

Animals↗
PubMed1985

Stability of solutions of antineoplastic agents during preparation and storage for in vitro assays. General considerations, the nitrosoureas and alkylating agents.

In vitro drug sensitivity of tumour biopsies is currently being determined using a variety of methods. For these chemosensitivity assays many drugs are required at short notice, and this in turn means that the drugs must generally be stored in solution. There are, however, a number of potential problems associated with dissolving and storing drugs for in vitro use, which include (a) drug adsorption; (b) effects of freezing; (c) drug stability under the normal conditions of dilution and setting up of an in vitro assay; and (d) insolubility of drugs in normal saline (NS) or phosphate-buffered saline (PBS). These problems are considered in general, and some recommendations for use of solutions of drugs in in vitro assays are suggested. The nitrosoureas and alkylating agents are also investigated in greater detail in this respect. The nitrosoureas are found to be very labile in PBS at pH 7, with 5% degradation (t0.95) occurring in 10-50 min at room temperature. These values are increased about 10-fold on refrigeration and about 5- to 10-fold on reduction of the pH of the medium to pH 4-5. At pH 7 and room temperature, t0.95 is observed in under 1 h with the alkylating agents nitrogen mustard, chlorambucil, melphalan, 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ), dibromodulcitol, dibromomannitol, treosulphan, and procarbazine. Of the other alkylating agents, 4-hydroperoxycylophosphamide (sometimes used in vitro in place of cyclophosphamide), busulphan, dianhydrogalactitol, aziridinylbenzoquinone (AZQ), and dacarbazine have a t0.95 of between 2 and 24 h, while ifosfamide and pentamethylmelamine are both stable in aqueous solution for greater than 7 days. About half the drugs studied in detail have been stored frozen in solution for in vitro use, although very little is known about their stability under these conditions.

Alkylation↗
PubMed1992

Phase II study of ACNU as second-line treatment in small-cell lung cancer. EORTC Lung Cancer Cooperative Group.

A total of 24 patients presenting with small-cell lung cancer either resistant to or relapsing within 3 months after first-line treatment were entered in a phase II study of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-(2-chloroethyl)-3- nitrosourea hydrochloride (ACNU). ACNU was given i.v. at a dose of 75 mg/m2 every 6 weeks. We observed a partial response of 7 months' duration in one patient and one case of stable disease that lasted for 6 months; all other subjects exhibited progressive disease. Two patients developed brain metastases during treatment. The toxicity of ACNU consisted mainly of bone marrow suppression, especially thrombocytopenia. At this dose and on this schedule, ACNU shows minimal activity as second-line treatment in small-cell lung cancer.

Carcinoma, Small Cell↗
PubMed1991

Phase II study of ACNU in non-small-cell lung cancer: EORTC study 08872.

A total of 62 patients with metastatic or locally advanced non-small-cell lung cancer were entered in a phase II study of ACNU. Initially, the drug was given i.v. at a dose of 100 mg/m2 every 6 weeks, but due to observed haematological side effects in chemotherapy-pretreated patients, the dose was lowered in this group to 75 mg/m2. We observed one complete response in a subject exhibiting multiple lung metastases and a partial response in two patients, one showing brain metastases and one who experienced local disease recurrence. The toxicity of ACNU mainly consisted of bone marrow suppression especially thrombocytopenia, with one toxic death occurring due to intracerebral haemorrhage. We concluded that at this dose and on this schedule, ACNU has limited activity in non-small-cell lung cancer.

Adult↗
PubMed1993

Identification of placental form of glutathione S-transferase in ACNU-resistant murine glioma cell lines.

Expression of the placental form of glutathione S-transferase (GST-P) in 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloro-ethyl)-3-nitrosourea hydrochloride (ACNU)-sensitive 9L and C6 glioma cells, and ACNU-resistant 9L (9LR) and C6 (C6R) glioma cells was investigated by Northern blot analysis for GST-P mRNA and Western blot analysis for GST-P protein. The sensitivity of 9L, 9LR, C6 and C6R cell lines to ACNU was evaluated by microculture tetrazolium assay. Localization of GSTP-P protein in these cell lines was investigated by immunocytochemical method. Expression level of GST-P mRNA in 9LR cells was 3 times that of 9L cells and the level of GST-P protein in 9LR cells was 1.7 times that of 9L cells. On the contrary, the amount of GST-P mRNA of C6R cells was 1.3-fold larger than C6 cells and that of GST-P protein of C6R cells was 1.3-fold larger than C6 cells. Immunocytochemical investigation revealed that 9LR cells had stronger expression of GST-P in their cytoplasm than 9L cells. Expression of GST-P in both C6R and C6 cells was less than 9L and 9LR cells, and the amount was similar to each other. The present study suggests that GST-P may play an important role in detoxification of anti-cancer drugs in some glioma cells.

Animals↗
PubMed1993

Characterization and chemosensitivity of two cell lines derived from human glioblastomas.

We have characterized two human glioblastoma cell lines, which were designated as YH cells and AM cells. The two cell lines maintained morphological appearance observed in the primary culture and immunohistochemically expressed glial fibrillary acidic protein (GFAP) and S-100 protein. Population doubling time for YH cells and AM cells indicated 30 hours and 25 hours, respectively, in an exponential phase of culture. Inoculation of AM cells into athymic nude mice formed large tumors at a high incidence. As with chemosensitivity to chloroethylnitrosourea, O6-methylguanine-DNA methyltransferase (MGMT) activity was measured in in vitro cultured cells as well as tumor specimens obtained at surgery. YH cells showed a high MGMT activity of 1196 fmol/mg and drug resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea hydrochloride (ACNU) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. YH tumor specimens indicated an MGMT activity of 301 fmol/mg, which reflected poor effectiveness of ACNU chemotherapy in the clinical evaluation. AM cells had an extremely low MGMT activity of 16 fmol/mg and were vulnerable to ACNU. Original tumor specimens of AM cells however expressed a high value of 628 fmol/mg. Considering that ACNU chemotherapy was not effective in the both patients, an MGMT activity of original tumors related with responsiveness to ACNU. Discrepancy in an MGMT activity between the in vitro cell lines and the respective tumor specimens comes from selection of ACNU-sensitive cells or alteration in biological characteristics during long term culture. These results suggest that cell lines derived human brain tumors are useful targets for understanding the chemosensitivity of human malignant gliomas and for establishing a pertinent chemosensitivity test.

Animals↗
PubMed1994

Enhancement of ACNU cytotoxicity by pretreatment with O6-methylguanine in ACNU-resistant brain tumors.

O6-Methylguanine is a substrate of the DNA repair enzyme O6-methylguanine-DNA methyltransferase, which is involved in the repair mechanism of DNA damage induced by chloroethylnitrosoureas such as 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). We tested the enhancement effect of O6-methylguanine pretreatment on ACNU cytotoxicity in ACNU-resistant brain tumors. Exposure to O6-methylguanine at various times ranging from 2 to 48 hours increased the cytotoxic effects of ACNU on C6-1 cells, and this effect was highest at higher concentrations 500 and 1,000 microM. Colorimetric cytotoxicity assay revealed at least a two-fold increase in ACNU cytotoxicity relative to controls without O6-methylguanine. Intraarterial ACNU after treatment with O6-methylguanine (two intravenous bolus injections of 80 and 40 mg/kg) significantly (P < 0.05 or P < 0.01) reduced the proliferation activity of transplanted C6-1 tumors for 96 hours after injection, whereas intravenous ACNU together with O6-methylguanine significantly (P < 0.05) reduced C6-1 activity for only 48 hours. Thus, pretreatment with O6-methylguanine prolonged the suppression effect of ACNU. The C6-1 tumors treated only with intravenous or intraarterial ACNU showed transient inhibition and rapid regrowth for 24 hours after treatment. These results indicate that O6-methylguanine increases ACNU cytotoxicity in an in vitro and in vivo brain tumor model.

Animals↗
PubMed1994

O6-alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications.

Activity of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) is an important determinant of responsiveness of tumor cells to chloroethylnitrosoureas (CENUs), representative chemotherapeutic agents for primary malignant gliomas. In order to assess the real states of this repair protein in human malignant gliomas, we assayed AGT activity in surgically extirpated 42 malignant glioma samples and studied the distribution of the activity under certain clinical conditions. There were wide variations in AGT activity between individuals. No significant difference in AGT activity on average was seen either between glioblastoma and anaplastic astrocytoma, nor between primary and recurrent tumors. Among 42 malignant gliomas, 7 samples (16.7%) had low AGT activity less than 0.1 pmoles/mg protein. In the case of glioblastoma, tumors possessing higher AGT activity tended to be less responsive to post-operation remission-induction therapy including CENUs. The result of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) chemosensitivity assay by using the corresponding surgical specimens suggested a close relationship between cellular resistance to CENUs and AGT activity. It was found to be unlikely that a short term administration of CENUs had a significant effect on AGT activity of brain tumors in human body. We could detect a bit of definite evidences of the relevance of AGT to resistance to CENUs and need to conduct further investigations for other resistance factors.

Astrocytoma↗
PubMed1994

Radiation therapy combined with radiosensitizing agents for cerebral glioblastoma in adults.

We analyzed our treatment results of 71 operated patients with cerebral glioblastoma treated by conventional external radiation therapy (mean dose 60.2 Gy) combined with radiosensitizing agents. More than 50% reduction of tumor volume was obtained in 20 patients (28.2%). A response rate of at least 40% was obtained in patients treated with combined ACNU-vincristine-nicardipine, ACNU-5FU-hydroxyurea, or cisplatin alone. The combination of ACNU and vincristine with or without nicardipine resulted in significantly longer survival. The median survival in this group was 101.1 weeks and the two-year survival rate was 45.9%; these results were significantly better than those achieved with other ACNU combinations or other combinations without ACNU. In the analysis of survival, factors correlated to longer survival were a patient age of younger than 45 years, wide resection of the tumor, a good postoperative performance status (KS > or = 70%), a radiation dose of 68-72 Gy, small postoperative tumor remnants (< 20 cm3), no visible tumor after radiation therapy, and the administration of adjuvant chemotherapy. Maximum resection of the tumor and localized irradiation with a dose of 70 Gy combined with ACNU and vincristine appears to be the most effective treatment at present.

Adolescent↗
PubMed1994

Neurotoxicity and pharmacokinetics of ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU) in dogs.

Ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), a water soluble nitrosourea with log P -0.71, may be efficacious in the treatment of subarachnoid dissemination of malignant glioma. We used 2 dogs to study the neurotoxicity and pharmacokinetics of MCNU. MCNU (1 mg), dissolved in 10 ml of artificial CSF, was administered via the right lateral ventricle during a period of 18 to 42 min and the CSF was drained by lumbar puncture. The perfusion was repeated once a week for 10 consecutive weeks. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord showed local denudation of the ependyma and local subependymal spongy degeneration and gliosis in the lateral ventricle into which MCNU was administered in one dog and local denudation of the ependyma in the other. When administration was over a period of 21 to 38 min, the MCNU concentration in the lumbar CSF peaked at 11.11 to 50.67 micrograms/ml, in 28 to 78 min. The area under the drug concentration-time curve (AUC) was 1152 micrograms x min/ml on average, significantly larger than that of ACNU. The elimination phase followed linear kinetics and the half-time was 41.1 min on average, significantly longer than that of ACNU. These findings suggest that ventriculolumbar perfusion of MCNU may be effective in the treatment of subarachnoid dissemination of malignant glioma notwithstanding some local histological changes.

Animals↗
PubMed1994

Pharmacokinetics of intrathecal 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride in rats.

The pharmacokinetics of intrathecal 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) were studied in female Wistar rats by macroscopical autoradiography using 14C labeled ACNU. In normal rats, ACNU rapidly distributed in the subarachnoid space and ventricles after intracisternal administration. Diffusional transport into the brain tissue was limited to a depth of 1 or 2 mm from the cerebrospinal fluid (CSF) surface of the brain. Clearance of ACNU from the CSF space and brain was relatively fast and the half time of ACNU concentration at the cortical or ventricular surface was 10 min. In rats with leptomeningeal tumor induced by intracisternal inoculation of Walker 256 carcinosarcoma cells, the distribution pattern of ACNU after intracisternal administration was essentially the same as in normal rats until the tumor had grown in the subarachnoid space to form more than 10 or 20 layers of tumor cells. ACNU was distributed in the tumor as well. When the tumor had grown to form masses in the subarachnoid space, ACNU failed to penetrate to more than a depth of 1 or 2 mm from the tumor surface. Our results suggest that intrathecal ACNU administration may have no, or minor side effects on the brain and that it can eliminate floating or thin layered tumor cells in the subarachnoid space but not bulky tumors.

Animals↗
PubMed1993

Intra-arterial mannitol infusion in the chemotherapy for malignant brain tumors.

To assess whether therapeutic efficacy is related to the intra-arterial (IA) mannitol infusion prior to ACNU and cisplatin (CDDP) for malignant brain tumors, the survival time of patients with and without mannitol infusion was compared. Ninety-eight patients were randomly assigned to either a mannitol infusion group (group A) or a non-mannitol infusion group (group B); 34 with malignant gliomas (18 in group A and 16 in group B) and 64 with brain metastases (36 in group A and 28 in group B). During radiotherapy, ACNU and CDDP at a dose of 100 mg/body were given through the common carotid artery at a rate of 20 mg/min. In group A, 50 ml of 20% mannitol was injected intra-arterially at a rate of 50 ml/min immediately prior to the injection of chemotherapeutic agents. Of the patients with malignant gliomas, the median survival time (MST) was 52 weeks for all 34 cases, 68 weeks for group A, and 47 weeks for group B. Survival analysis showed no significant differences between the two treatment groups. Of the patients with brain metastases, the MST was 40 weeks for all 64 cases, 47 weeks for group A, and 24 weeks for group B; the survival time was significantly longer in group A as compared to group B (p < 0.05). This study has demonstrated that, for the patients with brain metastases, IA mannitol infusion provided a survival benefit in the IA chemotherapy employing ACNU and CDDP. In contrast, IA mannitol infusion offered no survival benefit to the patients with malignant gliomas.

Adolescent↗
PubMed1993

Interrelationship between O6-alkylguanine-DNA alkyltransferase activity and susceptibility to chloroethylnitrosoureas in several glioma cell lines.

In order to study the dynamic relationship in glioma cells between O6-alkylguanine-DNA alkyltransferase (AGT) activity and resistance to the cytotoxic effect of chloroethylnitrosoureas (CENUs), we investigated the changes in sensitivity to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) after modulation of AGT activity. In ACNU-resistant rat glioma cell lines (9LR1, 9LR3, and 9LR12) and a human glioma cell (HNG-1), O6-methylguanine enhanced cytotoxicity to ACNU following a depletion of AGT activity. But no enhancement of cytotoxicity was seen in an ACNU-sensitive rat glioma cell line (9L). In the 9L and 9LR12 cells, equivalently sublethal doses of ACNU similarly depleted AGT activity but the regeneration rates of this repair protein were different. In the case of a 7-day pretreatment with human recombinant interferon-beta (HuIFN-beta), although it could modulate AGT activity in HNG-1 cells, no definite influence on cellular sensitivity to CENUs was observed. However, a 50-day pretreatment with HuIFN-beta conferred resistance to CENUs on them despite its effect to reduce AGT activity. Thus, diversity was seen in the relation between AGT activity and resistance to CENUs when AGT activity was modulated by HuIFN-beta. The results of this study suggest that AGT activity is one of factors affecting cellular sensitivity to CENUs but that alternative mechanisms of tolerance may be induced depending upon some environmental effects.

Animals↗
PubMed1994

Cell death due to ACNU-induced DNA fragmentation: inhibition by cycloheximide.

Several anticancer drugs have recently been shown to induce cell death in a manner similar to programmed cell death or apoptosis. The purpose of this study is to explore the mode of cell death caused by ACNU, a water-soluble nitrosourea. Exposure of rat glioma cell line KEG-1 to ACNU for 2 hours resulted in oligonucleosomal DNA fragmentation, creating a 'ladder' on agarose gel electrophoresis. DNA fragmentation began 18 hours after ACNU treatment, and preceded loss of membrane integrity as evaluated by the trypan blue exclusion test. The extent of DNA fragmentation increased in a dose-dependent manner, and the cell survival rate decreased reciprocally. A translational inhibitor, cycloheximide, suppressed this DNA fragmentation and enhanced cell survival rate with partial inhibition of protein synthesis. However, a transcriptional inhibitor, actinomycin D, failed to inhibit DNA fragmentation or enhance cell survival. Cycloheximide-inhibitable DNA fragmentation was also found in the KEG-1 implanted in vivo rat model following the administration of ACNU. These findings suggest that ACNU induces cell death associates with DNA fragmentation and partially with protein synthesis.

Animals↗
PubMed1995

Leukoencephalopathy associated with intra-arterial ACNU in patients with gliomas.

Thirty cases of gliomas treated by surgery, radiotherapy and intra-arterial (IA) ACNU were reviewed with a focus on the late side-effect known as leukoencephalopathy. All cases were classified into three groups; remission (10 cases), regrowth (15 cases) and leukoencephalopathy (5 cases) from their outcome. The average total doses of IA ACNU were 49.8 mg/sqm body surface area in the remission group, 157.3 mg/sqm in the regrowth group and 203.1 mg/sqm in the leukoencephalopathy group. There were significant differences in the total IA ACNU doses between the remission group and both regrowth and leukoencephalopathy groups, while no significant differences were noticed in the dose of radiation given. There was a correlation between the total dose of IA ACNU and the occurrence of leukoencephalopathy. An autopsy of a typical case of leukoencephalopathy revealed various degrees of myelin breakdown and thickening of arterial walls, which probably manifested progressive dementia accompanied by urinary incontinence and gait disturbance.

Adolescent↗
PubMed1985

Pharmacokinetic approaches to drug distribution in the cerebrospinal fluid based on ventricular administration in beagle dogs.

Two mathematical approaches are described to approximate the distribution of compounds (e.g., drugs) in the cerebrospinal fluid (CSF) downstream of or distal to both the ventricular injection site and the cisterna magna sampling site. The first approach uses a graphic representation and is, in essence, model independent; the second approach considers the geometry and physiology of CSF distribution and clearance. In all studies, radiolabeled inulin was used as an "internal standard" since it is not metabolized and is eliminated from the CSF primarily by bulk flow. Temporal comparison of the study compound to radiolabeled inulin in the cisternal CSF allowed testing of these models in beagle dogs. One use of this data is in the estimation of the drug exposure integral for antineoplastic drugs administered in the CSF to treat leptomeningeal neoplasia.

Animals↗
PubMed1994

A long surviving case of recurrent medulloblastoma displaying effectiveness of ACNU/vincristine chemotherapy.

A favorable case of recurrent medulloblastoma, in which 19 years has elapsed with combination therapy due to surgery, radiation and chemotherapy since the initial operation, is reported. The case was a male of age 12 who was admitted due to medulloblastoma of the classical type. Tumor recurrences were observed 3 times within 7 years after the initial operation and radiation treatment. At the 3rd recurrence, a large tumor was found in the cerebellar vermis and left cerebellar hemisphere on CT with CSF dissemination and a high NSE level in the CSF (62 ng/ml). Only chemotherapy by intravenous administration of 2 courses of 120-150 mg ACNU (1.7-2.2 mg/kg) and 4 mg vincristine (0.06 mg/kg) with intrathecal administration of methotrexate was given at this time. The tumor image and gait disturbance with radicular pain disappeared completely and the NSE level in the CSF improved to within the normal range (5.4 ng/ml). The patient continues in complete remission, with a Karnovsky performance status of 100% at 4 years after the 3rd recurrence. We report full details of this case in which active treatments consisting mainly of chemotherapy proved to be effective for recurrent medulloblastoma, even though its prognosis is generally very unfavorable.

Adult↗
PubMed1992

Malignancy and viability of intraparenchymal brain tumours: correlation between Gd-DTPA contrast MR images and proliferative potentials.

The feasibility of diagnosing the malignancy and viability of intraparenchymal brain tumours using Gd-DTPA, enhanced and unenhanced T1-weighted MRIs was investigated. The relationship between the Gd-DTPA enhancement pattern, the growth fraction (GF) determined by using the anti-bromide-oxyuridine (BrdU) monoclonal antibody, the clinical condition, the proliferative potential and the change of Gd-DTPA enhancement over time was studied. Forty-five patients with intracranial tumours were studied with the static method of Gd-DTPA MRI. The enhanced effect in Gd-DTPA MRIs was dependent on tumour-cell density, vascularization, necrosis, and dilatation of vascular lumen. Tumour-cells were observed in eighty-seven of eighty-nine specimens taken from areas with Gd-DTPA enhanced MRIs. Seventy-four percent of these specimens (64 of 87) showed a malignancy of more than 5% growth fraction. On the other hand, tumour cells were observed in twenty-seven of fifty-six specimens taken from areas with Gd-DTPA unenhanced MRIs. Eighty-five percent of these specimens (23 of 27) showed a malignancy value of less than 5% GF. However, fifteen percent of these specimen showed values between 5 and 15% GF. In the kinetic study of Gd-MRIs five patients who were in a clinically stable condition and one patient who had radionecrosis showed a constant pattern of enhancement or slightly increased enhancement 30 min after injection compared to 4 min after injection. Therefore, GD-DTPA MRI can be used effectively in the diagnosis of tumour viability and malignancy after treatment.

Brain↗