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PubMed2005

Local drug delivery in recurrent malignant gliomas.

In recurrent malignant gliomas, we scheduled a protocol by adding to systemic temozolomide a local treatment delivered through a reservoire positioned in the surgically created cavity, consisting of either mitoxantrone, liposome-loaded doxorubicine or nimustine (ACNU). The progression-free survival (PFS) and survival time (ST) of the whole group of 112 patients were 8.3 and 11 months, respectively, in GBM patients, and 14 and 18 months in AA patients. To limit the selection bias in recruitment we matched locally treated patients with the whole group of patients treated for 3 years and having undergone the same protocol with the exception of local drug delivery. Variables such as age, histology and local chemotherapy delivery were proved to be statistically significant independent factors on adjunctive PFS and ST. Another group of 12 recurrent malignant gliomas with further progression was locally managed according to convection-enhanced delivery (CED) of mitoxantrone; the preliminary results show good tolerability of the schedule.

Adolescent↗

PubMed2005

Amelanotic malignant melanoma of the esophagus: report of a patient with recurrence successfully treated with chemoendocrine therapy.

We report a case of primary amelanotic malignant melanoma of the esophagus, an extremely rare disease. A 58-year-old man was diagnosed as having middle esophageal cancer with lymph node metastasis, which was classified as esophageal cancer, Stage III:T3N1M0, by International Union Against Cancer (UICC) criteria. Preoperative chemotherapy was performed, but the response assessment was no change (NC). The patient underwent a subtotal esophagectomy via right thoracotomy and laparotomy. Reconstruction was performed by pulling up the stomach via the retrosternal route; the site of anastomosis was the neck. Adjuvant chemotherapy consisted of five courses of dacarbazine (DITC), nimustine (ACNU), vincristine (VCR), and interferon-beta. Eleven months after the surgery, computed tomography (CT) demonstrated recurrence in the upper mediastinum. The patient received chemoendocrine therapy, consisting of the first planned course of DITC, ACNU, and cisplatin (CDDP), given intravenously; and tamoxifen (TAM), given orally. Subsequently with a modified regimen of this therapy he attained a complete response (CR). In general, the prognosis of esophageal malignant melanoma is very poor. Although our patient had a recurrence, he is alive 4 years and 5 months after the surgery and 3 years and 6 months after the recurrence. The chemoendocrine therapy probably contributed to this outcome.

Antineoplastic Agents, Hormonal↗

PubMed2004

Immunohistochemical study for O6-methylguanine-DNA methyltransferase in the non-neoplastic and neoplastic components of gliomas.

Although the expression O6-methylguanine-DNA methyltransferase (MGMT) is an important hallmark for decision of nitrosourea chemotherapy for glioma patients, no immunohistochemical method for analysis of MGMT has been standardized yet. Gliomas usually contain non-neoplastic cells even deep in the tumor. It is not known which of these components expresses MGMT. To clarify this point, we investigated MGMT expression in the non-neoplastic cells in autopsy and surgical specimens by immunohistochemistry. High grade gliomas were also studied to find a cut-off point for treatment decision. MGMT immunohistochemistry in the normal brain or brain with non-neoplastic disease revealed nuclear staining in some endothelial cells, inflammatory cells, ependymal cells, astrocytes and oligodendroglias. Some cells were double stained with CD68 (macrophages or microglias). The neurons were consistently MGMT-negative. High grade gliomas always contained an MGMT-positive non-neoplastic component. Although, the endothelial cells were easily distinguished from the neoplastic cells, other cells were often mistaken for tumor cells. The population of MGMT-positive non-neoplastic cells was usually less than 10%. We set a cut off-point at 10% between the positive and negative groups because the statistical difference in the overall survival was most distinct at this value. In 51 high grade glioma patients, who received both radiotherapy and chemotherapy with nimustine (ACNU), the median overall survival of the MGMT-negative group (23 months) was significantly longer than that of the MGMT-positive group (14 months) (P < 0.009). Multivariate analysis revealed that the negative MGMT expression was a significant prognostic variable next to the degree of surgical removal for the overall survival. In the MGMT-positive group, addition of platinum-based chemotherapy did not improve the survival.

Aged↗

PubMed2006

Safety and efficacy of convection-enhanced delivery of ACNU, a hydrophilic nitrosourea, in intracranial brain tumor models.

Convection-enhanced delivery (CED) is a local infusion technique, which delivers chemotherapeutic agents directly to the central nervous system, circumventing the blood-brain barrier and reducing systemic side effects. CED distribution is significantly increased if the infusate is hydrophilic. This study evaluated the safety and efficacy of CED of nimustine hydrochloride: 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), a hydrophilic nitrosourea, in rat 9 L: brain tumor models. The local neurotoxicity of ACNU delivered via CED was examined in normal rat brains, and the maximum tolerated dose (MTD) was estimated at 0.02 mg/rat. CED of ACNU at the MTD produced significantly longer survival time than systemic administration (P < 0.05, log-rank test). Long-term survival (80 days) and eradication of the tumor occurred only in the CED-treated rats. The tissue concentration of ACNU was measured by high-performance liquid chromatography, which revealed that CED of ACNU at the dose of 100-fold less total drug than intravenous injection carried almost equivalent concentrations of ACNU into rat brain tissue. CED of hydrophilic ACNU is a promising strategy for treating brain tumors.

Animals↗

PubMed1987

Randomized controlled study of the effect of adjuvant immunotherapy with Picibanil on 51 malignant gliomas.

During the period from January 1981 to December 1983, two groups of a total of 51 patients (31 malignant astrocytomas, 17 glioblastomas, and 3 others) were treated with radioimmunochemotherapy using nimustine hydrochloride (ACNU) plus Picibanil (OK-432) (group A) and radiochemotherapy with ACNU only (group B) in a randomized controlled study. Group A consisted of 24 patients and group B of 27 patients. The differences in the background of the two groups were not statistically significant. Survival curves of both groups were shown by the Kaplan-Meier method. The postoperative survival rate at 1 year and 3 years was 70% and 30%, respectively, equal in both groups, and the differences between groups A and B were not statistically significant by the Cox-Mantel test. The side effects seen in group B were most prominent in the bone marrow, and severe leukopenia occurred. However, in group A leukopenia was suppressed after 2 months. Immunologic parameters, such as the purified protein derivative skin reaction test, did not change, but the streptococcus pyogenes Su-strain polysaccharide skin-reaction test became more positive after therapy in group A.

Adult↗

PubMed1988

Preliminary experimental results with the nitrosourea derivative ACNU in the treatment of malignant gliomas.

Comparative studies were carried out to evaluate the cytotoxic effectiveness of the nitrosureas ACNU (Nimustine) and BCNU (Carmustine) at equitoxic dose levels in xenografts from two astrocytomas grades III/IV (Li, Re) and one oligodendroglioma grade III (Oe) on nude mice. Growth delay was measured as the endpoint. All tumours were characterized initially and at regular intervals in later passages as to their histomorphologic pattern, expression of glial fibrillary acid protein and DNA-content by means of flow cytometry. These characteristics were shown to be unchanged in our xenografts over more than 27 passages. Growth delays of 18.7 days (ACNU) and 2.4 days (BCNU) for the Li-xenograft (p less than 0.01) were observed at an LD10 for both drugs. For the Re- and Oe-xenografts, growth delays of 18.0 vs. 14.0 days (p less than 0.001) and greater than 27.0 vs. 14.2 days (p less than 0.02) were observed at an equitoxic dose of 33 mg/kg ACNU or BCNU i.p., respectively. These preclinical data suggest a therapeutic advantage with ACNU for these high grade gliomas and should encourage further experimental and clinical investigations.

Animals↗

PubMed1995

Chemotherapy for progressive pilocytic astrocytomas in the chiasmo-hypothalamic regions.

Over the past 25 years, we have treated 17 patients with chiasmo-hypothalamic astrocytomas. Before 1988, the initial treatments consisted of surgery and/or radiotherapy, while since 1989, 4 children (1 male, 3 females, aged 3-8 years) were treated primarily with chemotherapy. None of them was associated with neurofibromatosis. After a biopsy of the tumor, the intravenous administration of ranimustine (MCNU; 30-86 mg/m2) and/or nimustine (ACNU; 30.3-64.1 mg/m2) was given without radiation therapy. Chemotherapy was usually given as an out-patient, with a total of 5-13 courses. The total doses of MCNU and ACNU administered ranged from 150 to 570 mg and from 64.8 mg to 100 mg, respectively. After chemotherapy 2 patients showed clinical improvement and tumor regression on neuro-imaging, while one patient showed clinical improvement and tumor size stabilization on neuro-imaging. The remaining one child, however, showed a clinical worsening and tumor progression on neuro-imaging studies. He was thus treated with a second chemotherapy regimen with carboplatin and etoposide, which brought about tumor regression. The acute and subacute toxicity of chemotherapy was mild. All patients are now leading almost normal lives with a median of 43 months after diagnosis. Although a longer and more careful clinical observation is required, the authors conclude that chemotherapy with MCNU and/or ACNU may benefit patients with unresectable pilocytic astrocytoma requiring treatment. The advantages of this therapy include its mild side effects and the lack of any hospitalization in most patients. It may also delay the need for radiation therapy, which can have a deleterious effect on the young developing brain.

Antineoplastic Agents↗

PubMed2000

Poly(ADP-ribose) polymerase-independent potentiation of nitrosourea cytotoxicity by 3-aminobenzamide in human malignant glioma cells.

Poly(ADP-ribose) polymerase is a zinc-finger DNA-binding protein that detects specifically DNA strand breaks generated by genotoxic agents and is thought to be involved in DNA repair. Here, we examined the effects of 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, on the chemosensitivity of human malignant glioma cells. 3-Aminobenzamide selectively potentiated the cytotoxicity of the nitrosoureas, nimustine, carmustine and lomustine in 10 of 12 human malignant glioma cell lines. In contrast, 3-aminobenzamide did not modulate the cytotoxic effects of doxorubicine, teniposide, vincristine, camptothecin or cytarabine. The nitrosoureas did not induce poly(ADP-ribose) polymerase activity in the glioma cells. Ectopic expression of truncated poly(ADP-ribose) polymerase containing the poly(ADP-ribose) polymerase DNA-binding domain, which acts as a dominant-negative mutant, in LN-18 or LN-229 cells did not alter the 3-aminobenzamide effect on nitrosourea-mediated cytotoxicity. Thus, 3-aminobenzamide may target another nicotinamide adenine dinucleotide (NAD)-requiring enzyme, but not poly(ADP-ribose) polymerase, when enhancing nitrosourea cytotoxicity in human malignant glioma cells. Carmustine cytotoxicity was associated with a G2/M arrest. Coexposure to carmustine and 3-aminobenzamide overcame this G2/M arrest in T98G cells, which are sensitized to carmustine by 3-aminobenzamide, but not in U251MG cells, which are refractory to 3-aminobenzamide-mediated sensitization to carmustine. Thus, 3-aminobenzamide-mediated sensitization to carmustine cytotoxicity may result from interference with the stable G2/M arrest response to carmustine in human glioma cells.

Benzamides↗

PubMed2000

Enhancing effect of electric stimulation on cytotoxicity of anticancer agents against rat and human glioma cells.

Electropermeabilization, or electroporation, has been used to deliver genes or drugs into the cytoplasm through micropores in the cell membrane caused by electric stimulation. The cytotoxic effect of a combination of anticancer agents with electric stimulation on rat C6 and human T98G glioma cells was examined in vitro. Electric pulses of 100 microsec square waves (eight cycles at 1 Hz) at various electric fields were delivered to C6 or T98G glioma cell suspensions in combination with several anticancer agents. Cell growth was evaluated 48-72 h after treatment. Measurement of cell lysis by electric stimulation was used to assess the optimum field strength for electroporation. Electric stimulation enhanced significantly the cytotoxicity of bleomycin to both C6 and T98G cells by more than 1000-fold using an electric field of 1750 V/cm for C6 cells and 1000 V/cm for T98G cells. The enhancement disappeared when bleomycin concentration was reduced to 100 pg/ml. The cytotoxicity of carboplatin was weakly but significantly enhanced by electric stimulation when a high dose of carboplatin was used. However, there was no enhancement of the cytotoxicity of nimustine hydrochloride (ACNU), etoposide, and vincristine. These results indicate that the combination of bleomycin and electroporation is the most potent candidate for electrochemotherapy in vivo.

Animals↗

PubMed1997

Transgenerational effects of maternal exposure to chemicals on the functional development of the brain in the offspring.

In order to prevent health risk from environmental chemicals, particularly for progeny, we have been performing a risk assessment for various chemicals including therapeutic agents. This paper reports the functional effects of maternal exposure to psychoactive drugs, anticancer drugs, or herbicides on the offspring of rats. Maternal exposure to imipramine in a dose equivalent to the therapeutic dose per unit body weight induced hyperthermic response to chlorpromazine in the male offspring, while normal control rats showed a marked hypothermia. Exposure to ethosuximide resulted in an increase in play fighting behavior in young offspring that was fostered by lactating normal mothers. Single exposures to nimustine or cisplatin, anticancer drugs, at a different gestational stage resulted in an acceleration of growth when exposed at the earlier stage of gestation. Moreover, cisplatin-exposed rats were emotionally unstable, showing a short latent time to the first line-crossing in an open-field during infantile period. The rats exposed to glufosinate ammonium, an herbicide, during the time of neurogenesis in the hippocampus showed a decrease in the wet-dog shakes response to kainic acid at six weeks of age. These results suggest that maternal exposure to chemicals during pregnancy induces a variety of functional abnormalities in the brain of the offspring dependent on the pharmacologic action of chemicals and the stage of gestation even with a single exposure.

Aggression↗

PubMed2006

Phase II trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas.

We conducted a phase II trial to evaluate the efficacy and toxicity of radiotherapy immediately after hyperbaric oxygenation (HBO) with chemotherapy in adults with high-grade gliomas. Patients with histologically confirmed high-grade gliomas were administered radiotherapy in daily 2 Gy fractions for 5 consecutive days per week up to a total dose of 60 Gy. Each fraction was administered immediately after HBO with the period of time from completion of decompression to irradiation being less than 15 min. Chemotherapy consisted of procarbazine, nimustine (ACNU) and vincristine and was administered during and after radiotherapy. A total of 41 patients (31 patients with glioblastoma and 10 patients with grade 3 gliomas) were enrolled. All 41 patients were able to complete a total radiotherapy dose of 60 Gy immediately after HBO with one course of concurrent chemotherapy. Of 30 assessable patients, 17 (57%) had an objective response including four CR and 13 PR. The median time to progression and the median survival time in glioblastoma patients were 12.3 months and 17.3 months, respectively. On univariate analysis, histologic grade (P=0.0001) and Karnofsky performance status (P=0.036) had a significant impact on survival, and on multivariate analysis, histologic grade alone was a significant prognostic factor for survival (P=0.001). Although grade 4 leukopenia and grade 4 thrombocytopenia occurred in 10 and 7% of all patients, respectively, these were transient with no patients developing neutropenic fever or intracranial haemorrhage. No serious nonhaematological or late toxicities were seen. These results indicated that radiotherapy delivered immediately after HBO with chemotherapy was safe with virtually no late toxicity in patients with high-grade gliomas. Further studies are required to strictly evaluate the effectiveness of radiotherapy after HBO for these tumours.

Adult↗

PubMed1996

Effect of recombinant human thrombopoietin in nonhuman primates with chemotherapy-induced thrombocytopenia.

We examined the effects of recombinant human thrombopoietin (rhTPO) on myelosuppressive chemotherapy-induced thrombocytopenia in cynomolgus monkeys. After treatment with nimustine (ACNU) on day 0, the monkeys intravenously received rhTPO at a dose of 0.04, 0.2 or 1 microgram/kg/d or monkey's serum once each day from day 1 to day 28. Administration of rhTPO reduced the severity of thrombocytopenia and accelerated the rate of platelet recovery in a dose-dependent fashion. Treatment with the highest rhTPO dose completely prevented thrombocytopenia and stimulated a marked increase in platelet counts over the normal values. Animals treated with ACNU also became neutropenic and slightly anaemic. Administration of rhTPO following ACNU treatment significantly improved neutropenia with increasing doses of rhTPO, but had no effect on anaemia. Compared to the control animals, rhTPO-treated animals exhibited no significant changes in several serum parameters. C-reactive protein concentration and some blood coagulation profiles within the study period. These results suggest a therapeutic efficacy of rhTPO in improving chemotherapy-induced thrombocytopenia.

Animals↗

PubMed2001

Primary malignant melanoma of the esophagus treated by esophagectomy and systemic chemotherapy.

We describe herein a case of asymptomatic primary malignant melanoma of the esophagus. A 65-year-old man presented with a 4-cm filling defect in the middle third of the esophagus on a routine barium swallow. Subtotal esophagectomy accompanied by lymph node dissection was performed through a right thoracotomy. Postoperatively, the patient received five cycles of systemic chemotherapy with dacarbazine (DTIC), nimustine hydrochloride (ACNU), and vincristine (VCR) (DAV therapy), but ultimately died of generalized metastatic disease 15 months after surgery. Malignant melanoma of the esophagus has an extremely poor prognosis despite various therapeutic efforts.

Aged↗

PubMed2000

Effectiveness of spray application of ACNU in the local control of malignant gliomas: report of two cases.

Malignant gliomas encompassing the eloquent areas cannot be removed totally and their surgical extirpation is followed by adjuvant therapy for the residual tumor. Recently, we have employed fibrin glue as a vehicle for the sustained release of ACNU (nimustine hydrochloride) by spray application following subtotal tumor removal in two patients with recurrent malignant gliomas. Follow-up MRI at six months demonstrated no neuroradiological evidence of tumor recurrence in the site of operation. We conclude, this novel mode of intra-operative local chemotherapy by spray application of fibrin glue containing antineoplastic agent is effective in the control of residual tumor progression and may also prevent local recurrence and hence suggests its possible role as an adjuvant therapy in the management of malignant gliomas.

Aerosols↗

PubMed2000

Thrombopoietic activity of recombinant human interleukin-11 in nonhuman primates with ACNU-induced thrombocytopenia.

The effect of recombinant human interleukin-11 (rHuIL-11) on myelosuppressive nimustine (ACNU)-induced thrombocytopenia was assessed in nonhuman primates. A single intravenous (i.v.) injection of ACNU (15 mg/kg) was administered to cynomolgus monkeys on day 0. rHuIL-11 (100 microg/kg/day) or the vehicle was given subcutaneously (s.c.) from day 1 to day 21. In monkeys receiving ACNU, the circulating platelet count decreased to a low of 42 +/- 6 x 10(9)/L by day 21 but returned to pretreatment levels (375 +/- 48 x 10(9)/L) on day 30. Administration of rHuIL-11 prevented severe thrombocytopenia; the platelet count fell only to 138 +/- 23 x 10(9)/L on day 18, and platelet recovery was faster (458 +/- 91 x 10(9)/L by day 27) compared with that of the control animals. The size of bone marrow megakaryocytes from rHuIL-11-treated animals was larger than that of the controls, indicating that rHuIL-11 stimulated megakaryopoiesis in a myelosuppressive condition. Treatment with ACNU also caused leukopenia and moderate anemia. rHuIL-11 transiently and slightly decreased the white blood cell (WBC) and red blood cell (RBC) counts. Conversely, rHuIL-11 accelerated recovery of RBC count in the late administration period. These results support the assertion that rHuIL-11 may be an important therapeutic agent for reducing the severity and duration of thrombocytopenia following cancer chemotherapy.

Animals↗

PubMed1998

Primary malignant melanoma of the esophagus: report of a case successfully treated with pre- and post-operative adjuvant hormone-chemotherapy.

Primary malignant melanoma of the esophagus is a very rare and deadly disease, with a survival of 2.2% at 5 years and a median survival of about 10 months. The aggressive biological behavior of this disease and advanced stage at the time of diagnosis together with the lack of effective treatment have contributed to its poor prognosis. We present the case of a 45-year-old Japanese man diagnosed as having a primary melanoma of the esophagus by clinical evaluation and a histological examination of endoscopic biopsy specimens. A novel approach consisting of pre- and post-operative chemo-hormone therapy with dacarbazine, nimustine, cisplatin and tamoxifen in conjunction with radical esophagectomy accompanied by lymph node dissection was carried out. The tumor size was decreased to 70% by the pre-operative chemo-hormone therapy. During the post-operative 32 months of follow-up, no evidence of recurrence or metastatic disease has been found. Although this is only one case, the outcome observed suggests that the combination of pre- and post-operative chemo-hormone therapy and radical esophagectomy with lymph node dissection is a modality that can increase the possibility of curability or at least improve the survival of patients with primary melanoma of the esophagus.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Successful treatment with ranimustine and carboplatin for recurrent intraocular retinoblastoma with vitreous seeding.

This is the first report of successful treatment of recurrent retinoblastoma with vitreous seeding by a combination of ranimustine (MCNU) and carboplatin. The patient was diagnosed with bilateral retinoblastoma at 3 years of age. Although he received photocoagulation and radiotherapy for the left eye after enucleation of the right eye, a recurrent tumor associated with vitreous seeding developed 6 years later. The child underwent chemotherapy with cyclophosphamide and nimustine hydrochloride (ACNU), and a transient decrease of tumor cells in the vitreous was seen. We then changed the chemotherapy regimen to MCNU (70 mg/m2/ day for 1 day) and carboplatin (400 mg/m2/day for 2 days). After five courses of this chemotherapy, the tumor in the vitreous completely disappeared. No recurrence has been observed for > 4 years. Side effects, including myelosuppression, general fatigue, and vomiting, were observed during the course of chemotherapy, but they were ameliorated with supportive therapy. Neither nephro- nor ototoxicity was observed. The patient has useful vision. These results warrant further study of this novel drug combination in patients with recurrent, or even primary, retinoblastoma.

Antineoplastic Agents↗

PubMedDate not supplied

FDG-PET as a prognostic indicator in radiochemotherapy of glioblastoma.

OBJECTIVE: We performed a prospective cohort study in a homogeneous patient group with proven glioblastoma who received uniform therapy to determine the prognostic value and clinical correlates of [18F]fluorodeoxyglucose (FDG) PET at different stages of the disease. MATERIALS AND METHODS: Fifteen newly diagnosed patients with glioblastoma, aged 52 +/- 9 years and with Karnofsky performance score (KPS) of at least 50, were treated with surgical resection, chemotherapy (nimustine), and radiotherapy. They were followed prospectively for 2 years. Clinical data (e.g., tumor progression, performance status, and survival) were recorded and glucose metabolism was measured with PET and FDG before and during radiochemotherapy. RESULTS: Median survival of all patients was 13 months and four patients were alive 24 months after surgery. All tumors were hypermetabolic compared with normal white matter. A metabolic index was calculated as the ratio of maximum residual tumor metabolism to contralateral normal brain metabolism. It was of prognostic value for patient survival and tumor recurrence already in the first postoperative and all following PET studies and was correlated with the KPS. Reduction of contralateral brain metabolism was more closely related to prognosis than the tumor metabolism proper. CONCLUSION: These results underscore the prognostic relevance of metabolically active residual tumor tissue after surgical resection.

Adolescent↗