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At least 253 records · Page 14Linked to original sources
PubMed1994

Potential of O6-methylguanine or O6-benzylguanine in the enhancement of chloroethylnitrosourea cytotoxicity on brain tumours.

The purine analogues O6-methylguanine and O6-benzylguanine are well-known as a chemical modulator of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. Inactivation of the enzyme by O6-methylguanine or O6-benzylguanine is expected to enhance sensitivity of tumours to chloroethylnitrosoureas. We studied the effect of O6-methylguanine or O6-benzylguanine pretreatment on cytotoxicity of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3- (2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) in brain tumour cells and transplanted brain tumours. Two-hour exposure of O6-methylguanine at higher concentrations (500 microM, 1,000 microM) increased ACNU cytotoxicity by only 2 times in ACNU-resistant C6-1 brain tumour cells. O6-Benzylguanine at concentrations between 10 and 100 microM markedly enhanced the cytotoxic effect. The ACNU sensitivity of the tumour cels pretreated with O6-benzylguanine was 5-40 times that of the cells without O6-benzylguanine. Neither O6-methylguanine nor O6-benzylguanine appreciably enhanced ACNU cytotoxicity of 9 L cells, which were originally sensitive to ACNU. Intracarotid ACNU with O6-methylguanine or O6-benzylguanine decreased proliferating activity of transplanted C6-1 brain tumours significantly during 48 hours. O6-Benzylguanine pretreatment resulted in a greater degree of suppression for a long time. The C6-1 tumours treated only with intracarotid ACNU showed a transient inhibition and a rapid regrowth during 24 hours after the treatment. These results indicate that O6-methylguanine or O6-benzylguanine increases ACNU cytotoxicity and may be feasible for effective combination therapy with chloroethylnitrosourea in the chemotherapy of malignant brain tumours.

Animals↗
PubMed1989

Complete remission of recurrent glioblastoma multiforme following local infusions of lymphokine activated killer cells. Case report.

We report the case of a 26-year-old man in whom glioblastoma multiforme had recurred six months following a subtotal resection. Despite radiotherapy and a course of interferon beta and ACNU, the tumour increased in size (to 3 cm) and there was neurological deterioration. Treatment was then initiated with LAK cells, together with ACNU and interferon beta. After three courses of LAK cells, tumour size was markedly reduced, and at about six months the tumour had nearly disappeared on computed tomographic (CT) scans. At one year, and after nine courses of LAK cell therapy (total dose of 2.7 x 10(9) cells) infused via an Ommaya reservoir and supplemented by ACNU and interferon beta, the tumour has disappeared and the patient is considered to be in complete remission since 6 months. This marked response is thought to be due chiefly to LAK cell therapy. The relatively low dose administered was well-tolerated.

Adult↗
PubMed1984

Treatment of malignant brain tumours with ACNU and phenobarbital: continuous infusion of ACNU into internal carotid artery and systemic administration of phenobarbital.

Thirteen patients with malignant brain tumours were treated by continuous intra-carotid infusion of ACNU in combination with systemic administration of phenobarbital. This aimed to maintain an ACNU concentration around the tumour cells higher for a relatively longer period and to make an ACNU concentration in the systemic circulation lower. Improvements on clinical states and CT findings were observed in 10 patients. The protective effect of phenobarbital against bone marrow suppression by ACNU was also suggested in this study. No complications were experienced in this treatment. This results strongly suggested that this technique is useful to treat patients with malignant brain tumours.

Adult↗
PubMed1987

Intracarotid infusion of ACNU and BCNU as adjuvant therapy of malignant gliomas. Clinical aspects and critical considerations.

Thirty patients with malignant gliomas were treated by operation, radiotherapy and additional intracarotid infusions of ACNU and BCNU. Positive results were obtained in the treatment of oligodendrogliomas and astrocytomas grade III and IV. On the contrary, the results in cases of glioblastoma multiforme were disappointing: neither survival time nor quality of life had been significantly improved. The protective effect of phenobarbitone against systemic toxicity by ACNU was not always confirmed in this study. Based on literature reports and our own experience the indications, technical aspects, unexpected complications and results of this therapeutic approach are discussed.

Astrocytoma↗
PubMed1991

In vitro studies on drug interaction of ifosfamide and ACNU in primary and metastatic human brain tumours.

Combination chemotherapy is widely employed in clinical oncology; however, there is no generally accepted model to evaluate individual tumour susceptibility to a given drug combination protocol. We therefore investigated the drug interaction of ifosfamide (4-hydroxyperoxy-ifosfamide) and ACNU in a recently developed in vitro model of paired sequential combination chemotherapy in primary and metastatic malignant brain tumours. A long-term standard [6,3-3H]-thymidine-incorporation assay, employing a liquid scintillation counting protocol, was selected to assess the drug sensitivity of human tumours. In vitro drug exposures were derived from correlating in vivo-(systemic and CNS) and in vitro-pharmacokinetic drug parameters. In combination experiments tumour cells were treated sequentially by two drugs in both sequences: drug exposures were calculated for 2 h with a 1-h drug-free interval in between. "Cut-off" concentrations (maximum in vitro exposure doses) were calculated as 1.74 microM (for primary CNS tumours: 0.58 microM) for ifosfamide and 5.4 microM (for primary CNS tumours: 1.33 microM) for ACNU. Dose/response relations were derived from isotope incorporation rates after cells had grown for approximately five population doubling times. Combination isoboles were plotted after drug doses had been transformed into "equieffective doses", enabling comparison of drug combination effects. In all three glioblastomas (with CNS exposure dose) an additive or supra-additive effect could be observed in either sequence (in one tumour a biphasic additive isobole was found for both sequences). Out of three bronchial carcinomas (small-cell type, brain metastases) in two non-identical sequences a supra-additive effect was observed in two tumours, with antagonistic effects in the third tumour. In all three malignant melanomas and in one renal carcinoma antagonistic effects were observed, whereas in a second renal carcinoma supra-additive effects were demonstrated for both sequences. We conclude that drug combination chemotherapy effects at the cellular level may be extremely heterogeneous.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Combined chemo- and radiosensitivity testing with ifosfamide and ACNU in human lung cancer cell lines.

The combination of radiotherapy and cytostatic drugs is of interest in the treatment of several solid tumors. In these preclinical investigations we tested whether ifosfamide and ACNU are able to enhance radiation effects. The experiments were performed by using the MTT assay. Two small cell and 2 non small cell lung cancer cell lines were involved. Ifosfamide, ACNU or both drugs together were tested in 6 different concentrations adjusted to the peak blood level. During the 1 hour drug incubation time, the cell lines were either irradiated with a single dose of 4 Gy or not. The main results were that ACNU possessed only little cytostatic activity in the cell lines under examination. In contrast, ifosfamide caused a dose related cytostatic activity in all cell lines. Concentrations of 26 micrograms/ml (NCC-SCLC H 82) or 10-12 micrograms/ml (3 other cell lines) were able to reduce the surviving cell fraction to less than 50% (IC50). While ACNU showed no clear outlined radiosensitizing properties, ifosfamide reinforced the radiation effects in 3 out of 4 cell lines indicating radiosensitizing properties of this drug. Synergistic effects of ifosfamide and ACNU have not been noticed. These preclinical investigations may constitute the basis for combined ifosfamide and irradiation therapy in future clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Ifosfamide and ACNU in experimental allogeneic bone marrow transplantation.

We have tested ifosfamide and ACNU for their effectiveness in preventing graft rejection following allogeneic bone marrow transplantation. The engraftment-promoting potency of both was compared to that of the standard agent cyclophosphamide. LEW rats received a lethal dose (35 mg/kg) of busulfan followed by injection of 1 x 10(8) (CAP x LEW) F1 marrow cells, which are unable to induce a graft vs host reaction in LEW recipients. Rejection of the marrow graft was assessed by monitoring haematocrit and granulocyte count either until death of the animal or until day 80. Surviving animals received a donor-type skin graft to confirm the persistence of allogeneic haematopoiesis. Because of its weak immunosuppressive properties, busulfan by itself is unable to allow engraftment of allogeneic marrow. Therefore, ifosfamide and ACNU and cyclophosphamide as the standard agent could be tested for their capacity to prevent marrow graft rejection. The following rejection rates were observed: cyclophosphamide: 30 mg/kg 100%, 60 mg/kg 60%, 90 mg/kg 20%, 120 mg/kg and 180 mg/kg 0%; ACNU: 3, 5, 7, and 10 mg/kg 100%, 15 mg/kg 45%, 20 and 30 mg/kg 0%; ifosfamide: 60-120 mg/kg 100%, 180 mg/kg 68%, 240 and 360 mg/kg 0%. Thus, 240 mg/kg ifosfamide or 20 mg/kg ACNU is nearly equivalent to the standard dose of 120 mg/kg cyclophosphamide in engraftment-promoting potency in allogeneic bone marrow transplantation.

Animals↗
PubMed1984

Intensive chemotherapy with autologous bone marrow rescue for recurrent malignant gliomas.

Eight patients, four male and four female, were treated with high dose chemotherapy followed by bone marrow transplantation. In the first two patients, high dose ACNU was used for the treatment without combination with other drugs. This showed severe side effects such as intratumorous bleeding on the 18th day of treatment in the first case and pulmonary fibrosis on the 35th day of treatment in the second case. Considering these results, we considered another treatment schedule which consisted of high dose ADM (100 mg/m2), VCR (1.5 mg/m2), CDDP (80 mg/m2 X 4) and Ex (800 mg/m2) within seven days. Six patients were treated with this schedule and the results indicated that two patients had a partial response (more than 50% reduction of tumour size measured by CT scan), one had a complete remission (no tumour detected by CT scan), two showed no change and one, progression of the lesion. The patients recovered from the suppression of bone marrow function after the bone marrow transplantation as indicated. Granulocytes and platelets in blood began to increase from 10 to 14 days after the transplantation and became normal within three weeks after this. Serial measurements of S-GOT and alkaline phosphatase revealed reversible elevation, if any, within four weeks of the treatment. The number of our cases is still small, but results showed that autologous bone marrow transplantation made high dose chemotherapy possible. The necessity for consideration of the blood-brain barrier for this treatment is also discussed.

Adult↗
PubMed1994

Long-term follow-up results of 175 patients with malignant glioma: importance of radical tumour resection and postoperative adjuvant therapy with interferon, ACNU and radiation.

We analysed long-term follow-up results of 175 patients with malignant glioma (110 glioblastoma and 65 anaplastic astrocytoma) treated under five different regimes during the past two decades. The factors of age (less than 40), histology (anaplastic astrocytoma) and type of adjuvant therapy (radiation and chemotherapy) contributed to long survival. The other important factor was the response to adjuvant therapy. Cases of gross total removal or complete response (CR) of a residual tumour to an adjuvant therapy showed a better prognosis. The three and five year survival rate was 42% and 24%, respectively. The highest CR ratio (23%) was seen in patients treated by intravenous injection of interferon and ACNU in addition to radiotherapy (IAR therapy).

Adolescent↗
PubMed1985

Suppression of natural killer activity in patients treated with cisplatin and methylprednisolone.

The achievable concentrations of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl-3-nitrosourea (ACNU), adriamycin, mitomycin C, vindesine, and epipodophyllotoxin suppressed the natural killer (NK) activity of human peripheral blood lymphocytes in vitro, whereas NK activity was not decreased 24 h after incubation with the maximum achievable concentration of cisplatin (cDDP). NK activity of patients treated with 80 mg per square meter of cDDP alone was not decreased for 3 weeks after cDDP administration. In contrast, NK activity of patients treated with the same dose of cDDP and methylprednisolone was significantly decreased 1 week after cDDP administration. It was concluded that methylprednisolone, used as an antiemetic agent, had an immunosuppressive effect.

Adult↗
PubMed1995

Plasma levels of IL-1, TNF alpha, IL-6, IL-8, G-CSF, and IL1-RA during febrile neutropenia: results of a prospective study in patients undergoing chemotherapy for acute myelogenous leukemia.

Plasma levels of IL-1, IL-6, IL-8, IL1-RA, TNF alpha, and G-CSF were prospectively studied during 23 chemotherapy cycles of 20 patients suffering from acute myelogenous leukemia. Increased plasma levels of IL-6, IL-8, and G-CSF were observed in patients with febrile neutropenia and/or major infection. Plasma levels of IL-6, IL-1, TNF alpha and IL-1-RA measured 1 day before and 1 day after the onset of febrile episodes did not accurately predict the development of major infection. In contrast, IL-8 plasma levels were significantly higher in those patients who subsequently developed major infection. The question whether IL-8 plasma levels identify high risk or low risk patients with sufficient specificity and sensitivity has to be answered in large scale clinical trials.

Adolescent↗
PubMed1987

Enhanced antitumor efficacy with a combination of hyperthermochemotherapy and thermosensitization with polyamine antimetabolites in nude mice.

In an attempt to enhance the antitumor effects of hyperthermochemotherapy, methylglyoxal-bis-guanylhydrazone (MGBG) and alpha-difluoromethylornithine (DFMO) were used in combination with hyperthermochemotherapy of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU) against human gastric cancer (ST-2) xenotransplanted into nude mice. After priming with DFMO and MGBG, ACNU was given ip and subsequently, a 23 minute-hyperthermia was carried out by placing the leg with the tumor into a water bath of a temperature of 43.5 +/- 0.1 degrees C. The second hyperthermic treatment was given in the same manner after 48 hours. MGBG and DFMO were administered for 4 successive days from the previous day of the first hyperthermia. In mice treated with DFMO plus MGBG, either tumor growth or tumor tripling time was much the same as in the control, while in mice given MGBG, DFMO plus heat, there was a diminution in tumor growth. Hyperthermia together with MGBG, DFMO plus ACNU brought about remarkable antiproliferative effects on ST-2 tumor growth, compared to three regimens with MGBG, DFMO plus heat, MGBG, DFMO plus ACNU, as well as ACNU plus heat. These data suggest that a combination of MGBG with DFMO leads to a favorable thermosensitization to the antitumor efficacy of ACNU.

Animals↗
PubMed1986

Combined therapy of polyamine antimetabolites and antitumor drugs for human gastric cancer xenotransplanted into nude mice.

Antitumor therapies using polyamine antimetabolites combined with 1-(4-amino-2-methyl-5-pyrimidyl)methyl-3(2-chloroethyl)-3-nitrosourea (ACNU) or fluorinated pyrimidines for human gastric cancer xenotransplanted into nude mice were studied to determine inhibiting post-therapeutic regrowth of the tumor after cessation of antitumor treatments with polyamine antimetabolites alone. ACNU 20 mg/kg, fluorinated pyrimidine, 5-FU 52.8 mg/kg and 5'-deoxy-5-fluorouridine (5'-DFUR) 100 mg/kg as well as polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) 1000 mg/kg and methylglyoxal-bis-guanylhydrazone (MGBG) 50 mg/kg were given intraperitoneally for 5 successive days. When DFMO and MGBG were combined with ACNU, the post-therapeutic regrowth was definitely inhibited, while combined treatments with 5-FU or 5'-DFUR did not inhibit the regrowth. Post-therapeutic DNA biosynthesis was suppressed in mice given DFMO, MGBG plus ACNU. On the contrary, in mice treated with DFMO, MGBG plus 5-FU or 5'-DFUR, suppression of DNA biosynthesis was not observed. Tumor tissue spermine levels in the DFMO, MGBG plus 5-FU or 5'-DFUR group remained unchanged, compared to those in the DFMO + MGBG group. In mice given DFMO, MGBG plus ACNU, however, spermine levels were markedly depressed; and the ACNU alone depressed also the tissue spermine levels. These different results between nitrosourea and fluorinated pyrimidines may relate to mechanisms of action of these antitumor drugs.

Animals↗
PubMed2000

Clinicopathological study of oligodendroglial tumors: the effectiveness of interferon beta, ACNU/MCNU, and radiation (IAR/IMR) for anaplastic tumors.

The retrospective clinicopathological characteristics of oligodendroglial tumors were investigated in patients who underwent surgery, radiotherapy, and/or chemotherapy. Regarding oligodendroglioma and oligoastrocytoma without malignancy, patients who had undergone radiation therapy at a total dose of 40-50Gy had relatively long postoperative survival. Of these 15 patients, 6 showed signs of recurrence, and after additional treatment, 5 patients are still alive. On the other hand, regarding anaplastic oligodendroglial tumors, patients with anaplastic oligoastrocytoma responded well to combination chemotherapy with interferon beta, nitrosourea derivatives (ACNU/ MCNU), and radiation therapy (referred to as IAR/IMR) and survived longer than patients with anaplastic oligodendroglioma. In conclusion, patients with oligodendroglial tumors could survive longer by treatment involving surgery and radiotherapy. As for malignancy, cases of anaplastic oligoastrocytoma could be effectively treated by adjuvant therapy using IAR/IMR after surgery, but in cases of anaplastic oligodendroglioma, the response to IAR/IMR was not good, and another strategy of treatment should be recommended.

Adolescent↗
PubMed2000

Actinomycin D and staurosporine, potent apoptosis inducers in vitro, are potentially effective chemotherapeutic agents against glioblastoma multiforme.

PURPOSE: Although chemotherapeutic protocols that include chloroethylnitrosoureas (CENUs), such as 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU), have been a mainstay of treatment for glioblastomas, the clinical outcomes have been unsatisfactory. More effective chemotherapeutic protocols for these tumors will require clear delineation of more cytocidal and cytostatic chemotherapeutic drugs. METHODS AND RESULTS: In this study, we measured the cytocidal effects of ACNU, cisplatin, actinomycin D, and staurosporine, administered within their therapeutic dose ranges, in the treatment of glioblastoma cells. As assessed by WST-1 colorimetric assay, the number of viable cells decreased markedly in T98G cultures treated with actinomycin D or staurosporine, to less than 20% of the level in control cultures at 72 h, but did not decrease or even increased after 6 days of treatment with ACNU. After treatment with cisplatin for 5 days, cell viability decreased to 30% of control. As assessed by fluorescence microscopic examination of nuclear staining by Hoechst 33258 and by electron microscopy, the majority of dead cells treated with actinomycin D, staurosporine, or cisplatin had morphologic features of apoptosis. Caspase-3 activity increased more than 20-fold in cells treated with actinomycin D, staurosporine, or cisplatin but increased less than fivefold in ACNU-treated cells. In addition to caspase-3 activation, western blot analysis demonstrated cleavage of caspase-2 during the apoptotic process. These findings indicate that actinomycin D and staurosporine potently induce apoptosis, whereas ACNU exerts mainly a cytostatic rather than a cytocidal effect. CONCLUSION: Actinomycin D and staurosporine and their derivatives are potentially effective chemotherapeutic agents against glioblastoma cells at least in vitro.

Antibiotics, Antineoplastic↗
PubMed1997

Immunohistochemical expression of P-glycoprotein and glutathione S-transferases in cerebral gliomas and response to chemotherapy.

The expression of the drug resistance-related proteins glutathione S-transferases (GST) and P-glycoprotein (Pgp) was analyzed quantitatively in samples of 53 astrocytic gliomas (eight WHO grade 1, 11 WHO grade 2, 9 WHO grade 3 and 25 glioblastomas, WHO grade 4). Sections of these tumors were immunohistochemically stained with antibodies to Pgp (MDR1-gene product) and to GST subclasses alpha, mu and pi. Pgp expression was not detected in tumor cells of the majority of low-grade astrocytomas (69%) and the percentage of Pgp stained cells generally increased with tumor grade. However, 4 of the 34 malignant gliomas were negative. Many neoplastic cells of most tumors were dominantly stained for GST-pi. The other two subclasses were expressed in a less consistent fashion with no linear correlation to grading. Grade 2 astrocytomas exhibited the highest percentage of cells with GST expression. GST-alpha was absent in 9 tumors, GST-mu in 8 and GST-pi in 4. Four tumors showed no expression of any GST subclass or Pgp in neoplastic cells. Of 13 patients 5 with a more favorable clinical course after radiation and chemotherapy had a lower percentage of neoplastic cells immunostained for Pgp and the three GST subclasses than 8 patients with a worse clinical course. These results suggest a relationship between expression of drug resistance-related proteins in gliomas and response to chemotherapy with ACNU/VM26.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Intra-arterial ACNU and carboplatin versus intravenous chemotherapy with cisplatin and BCNU in newly diagnosed patients with glioblastoma.

Thirty glioblastoma patients treated at our institute between April 1998 and September 1999 were randomized in a two-arm study to receive carboplatin plus ACNU intraarterial (IA) chemotherapy (arm A) or cisplatin plus BCNU intravenous (IV) treatment (arm B). After the second course of chemotherapy and before the third cycle they also received concomitant radiotherapy, consisting of a median dose of 56.5 Gy. There were 3 (21.4%) partial responses and 11 (78.6%) disease stabilizations in group A. There were 5 (33%) partial responses and 10 disease stabilizations in group B. Time to tumor progression was 5.2 and 5.8 months for IA and IV treatment respectively. Median survival time was 18.3 months for arm A patients and 18.6 for arm B patients. Our IA chemotherapy schedule has produced no conclusive evidence of benefit compared with intravenous treatment. Moreover, its cost-benefit ratio is not good enough to justify its continued pursuit.

Adolescent↗