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PubMedDate not supplied

Treatment of canine mast cell tumors with CCNU (lomustine).

The efficacy and toxicity of CCNU (1-[2-chloroethyl]3-cyclohexyl-1-nitrosourea) were evaluated in 23 dogs with measurable mast cell tumors (MCT). Twenty-two dogs had cutaneous MCT and 1 dog had an intranasal MCT Nineteen (83%) dogs had biopsy of their original mass performed and 4 (17%) had aspiration cytology of masses. Of the 19 tumors histologically graded, 1 (5%) neoplasm was classified as grade I, 10 (53%) were grade II, and the remaining 8 (42%) were grade III. Dogs were treated with CCNU at a dosage of 90 mg/m2 body surface area every 3 weeks. Response could be evaluated in 19 dogs. Eight of the 19 dogs (42%) had a measurable response to CCNU. One dog had a durable complete response for 440 days. Seven dogs (37%) had a partial response for a median and mean duration of 77 days and 109 days, respectively (range, 21-254 days). Treatment with CCNU resulted in stable disease in 6 dogs (32%) for a median and mean duration of 78 days and 122 days, respectively (range, 42-347 days). The acute dose-limiting toxicity was neutropenia 7 days after administration of CCNU. The median and mean neutrophil counts 7 days after CCNU were 1,452 cells/microL and 1,683 cells/microL, respectively (n = 17). Other toxicoses were uncommon. CCNU should be considered an active agent in the treatment of MCT in dogs.

Animals↗
PubMedDate not supplied

Phase I evaluation of CCNU (lomustine) in tumor-bearing cats.

1-(2-Chloroethyl)3-cyclohexyl-1-nitrosourea (CCNU) is an alkylating agent in the nitrosourea subclass. A prospective evaluation of CCNU was done to determine the maximally tolerated dosage of CCNU in tumor-bearing cats. Response data were obtained when available. Twenty-five cats were treated with CCNU at a dosage of 50-60 mg/m3 body surface area. Complete hematologic data were available for 13 cats. Neutropenia was the acute dose-limiting toxicity. The median neutrophil count at the nadir was 1,000 cells/microL (mean, 2,433 cells/microL; range, 0-9,694 cells/microL). The time of neutrophil nadir was variable, occurring 7-28 days after treatment, and counts sometimes did not return to normal for up to 14 days after the nadir. Based on these findings, a 6-week dosing interval and weekly hematologic monitoring after the 1st treatment with CCNU are recommended. The nadir of the platelet count may occur 14-21 days after treatment. The median platelet count at the nadir was 43,500 cells/microL. No gastrointestinal, renal, or hepatic toxicities were observed after a single CCNU treatment, and additional studies to evaluate the potential for cumulative toxicity should be performed. Five cats with lymphoma and 1 cat with mast cell tumor had measurable responses to CCNU. Phase II studies to evaluate antitumor activity should be completed with a dosing regimen of 50-60 mg/m3 every 6 weeks.

Administration, Oral↗
PubMedDate not supplied

Hepatotoxicity associated with CCNU (lomustine) chemotherapy in dogs.

One hundred seventy-nine tumor-bearing dogs were treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) between 1995 and 2001. CCNU was given as a single dose of 50-110 mg/m2 body surface area PO. Treatment interval varied, but the minimal interval between CCNU doses was 3 weeks. After treatment, 11 dogs (6.1%) developed hepatic toxicity. The median number of CCNU doses and the median total cumulative CCNU dose were significantly higher in dogs that developed hepatic toxicity (4 doses; 350 mg/m2) than in dogs without hepatic damage (3 doses; 230 mg/m2). Median duration to detection of hepatic toxicity from the last dose of CCNU was 11 weeks (range 2-49 weeks). Common biochemical abnormalities were abnormally high serum liver enzyme activities and hypoalbuminemia. Six dogs with CCNU-associated hepatic toxicity had ascites, and 3 dogs had concurrent pleural effusion. Serum concentrations of bile acids were abnormally high in 4 of 5 dogs tested. Percutaneous ultrasound-guided liver biopsies were performed in 10 dogs, and findings were nonspecific and chronic in nature. Seven dogs were euthanized because of progressive liver failure, and their median survival from diagnosis of liver disease was 9 weeks. Three dogs died of other causes and 1 dog of unknown cause. Although clinical signs resolved in 3 dogs, biochemical abnormalities and histopathologic lesions persisted 4 to 38 months from the time of diagnosis of liver disease. Our findings suggest that CCNU can cause delayed, cumulative dose-related, chronic hepatotoxicity that is irreversible and can be fatal.

Administration, Oral↗
PubMedDate not supplied

Response of canine cutaneous epitheliotropic lymphoma to lomustine (CCNU): a retrospective study of 46 cases (1999-2004).

BACKGROUND: Epitheliotropic lymphoma (ELSA) is an uncommon cutaneous canine malignancy of T lymphocytes. A consensus regarding the therapeutic standard of care is lacking, warranting evaluation of chemotherapeutic agents traditionally employed against canine nodal lymphoma in the treatment of ELSA. HYPOTHESIS: The purpose of this retrospective, multi-institutional study was to evaluate the efficacy of 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) in the treatment of ELSA. ANIMALS: Forty-six dogs with adequate follow-up and treatment response information. METHODS: All cases were diagnosed histopathologically. Immunohistochemisty (CD3, CD79a) was performed on 42/46 samples. RESULTS: Presenting skin lesions included generalized scales (25/46), plaques or nodules (22/46), mucocutaneous lesions (14/ 46), and corneal involvement (1/46). Lymph node involvement and Sézary syndrome were documented in 7 and 2 dogs, respectively. The median number of CCNU treatments was 4 (range, 1-11), with a median starting dose of 60 mg/m(2) (range, 30-95). Of the 46 dogs, 15 achieved complete remission, 23 achieved partial remission, 5 had stable disease, and 3 had progressive disease, for an overall response rate of 83%. The median number of treatments to achieve a response was 1 (range, 1-6). The overall median duration of response was 94 days (range, 22-282). Sixteen dose reductions were required because of neutropenia (10/46), thrombocytopenia (1/46), anemia (1/46), increased liver enzyme activity (3/46), or unspecified reasons (1/46). CONCLUSIONS AND CLINICAL IMPLICATIONS: Given the high response rate and well tolerated protocol, prospective studies are warranted to investigate the utility of CCNU alone or in multi-agent protocols for the treatment of ELSA.

Animals↗
PubMed2001

Lipid association improves the therapeutic index of lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] to suppress 36B-10 tumor growth in rats.

The therapeutic efficacy and tumor accumulation of a liposome formulation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), an effective agent used in the treatment of malignant brain tumors, was examined in an animal tumor model. Pharmacokinetic studies in normal and tumor-bearing rats indicated that a 2-fold greater plasma exposure was achieved with liposome-formulated CCNU compared with the free drug. In Fisher rats bearing s.c. tumors 36B-10, tumor growth was delayed substantially when liposomal CCNU was delivered compared with free-drug treatment. In single-dose treatments of 20, 35, and 50 mg/kg, tumor progression after each dose was reduced approximately 2-fold with liposomal compared with free CCNU (four animals in each treatment group). Multiple-dose treatments (given as three weekly doses with eight animals in each treatment group) with cumulative doses of 80 and 100 mg/kg of free and liposomal CCNU also resulted in a 2-fold reduction in tumor progression when compared with free-drug treatment. When drug levels in tumors relative to plasma were examined, it was observed that tumor drug concentrations did not exceed those found in plasma after administration of free CCNU; after administration of liposomal CCNU, however, tumor concentrations exceeded those in plasma by nearly 10-fold. These results suggest that the increased efficacy of liposome-formulated CCNU may be attributable to enhanced drug accumulation in tumor tissues.

Animals↗
PubMedDate not supplied

[Efficacy of lomustine, teniposide, doxorubicin, bleomycin and prednisone (LTABP) or adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) in the treatment of malignant lymphogranulomatosis resistant to MOPP].

LTABP regimen was applied to 18 patients in IIB and IV stage of malignant lymphogranulomatosis resistant to MOPP. The obtained results were compared with historical control group of 18 patients with similar stage of the disease treated according to ABVD regimen. In both regimens courses were repeated every 28 days or more rarely, when leucopenia and thrombocytopenia prolonged. Only patients who had received at least 3 courses were analysed. In the LTABP group the complete remission was obtained in 10 cases (55%) while partial remission in 6 (33%). In the group treated with ABVD complete remission was obtained in 4 cases (22%) and partial in 9 cases (50%). In the LTABP group 11 patients are still alive and remain in complete remission, while in ABVD group--4 patients. The most frequent side effects in both groups included leucopenia, thrombocytopenia and symptoms of gastrointestinal intolerance. The LTABP regiment allows to obtain higher percentage of the complete remission than ABVD.

Adolescent↗
PubMed1990

[The influence of CCNU (lomustine) on the neurosecretion of hypothalamic nuclei and the neurohypophysis during early stages of extrauterine development of the rat].

The hypothalamo-neurohypophyseal neurosecretory system was investigated in 8-, 15- and 30-day-old rats subjected to three intragastric doses of CCNU - 12.5 mg/kg b. wt. each on the 3rd, 5th and 7th day after birth. Neurosecretory neurons in the hypothalamus were visualized in the paraffin sections by the immunoenzyme (PAP) technique using antibodies against neurophysin and by Gomori chrome-hematoxylin staining. Accumulation of neurophysin was observed in these cells after treatment with CCNU. Karyometric measurements showed an increase of the mean nuclear cross-section area in PVN neurons in 8-day-old rats exposed to CCNU. In four experimental rats disseminated intracerebral hemorrhagic foci were present. Plasma osmolality was far below the normal values on the 8th day, on the 15th day of life it shifted to hyperosmolality and returned to normal at the age of 30 days. Discussion of the results leads to the conclusion that the increase of the neurosecretory function observed in this experiment was secondary to vasogenic changes.

Animals↗
PubMed1986

Morphological alterations in blood vessel endothelia of rat brain after administration of CCNU (lomustine).

Studies were performed on adult Wistar strain rats which were given four one-week spaced, intragastric doses of 2.5 mg or (the last dose) 5.0 mg CCNU. The animals were sacrificed one week after the last dose of the cytostatic drug. Cell nuclei of blood vessel endothelia in the parietal cerebral cortex and in the frontal-lateral part of the thalamus were examined. Karyo- and cytophotometric measurements were performed on sections subjected to Feulgen's reaction, using an automatic microscope image analyzer Morphoquant (Carl Zeiss, Jena). In CCNU-administered rats, blood vessel endothelia in the brain exhibited morphological alterations in the form of edema, increased DNA content in cell nuclei, modified distribution and density of chromatin lumps (nuclear chromatin lumps shifted towards the center of cell nucleus in the parietal cortex and in the thalamus, increased density of nuclear chromatin in the thalamus). Morphological alterations, changes in DNA content and in the nuclear chromatin status were of a similar type in blood vessel endothelia in the two examined structures but were somewhat more intense in endothelia of the cortex than in thalamus endothelia.

Animals↗
PubMed1986

MACC (methotrexate, doxorubicin, cyclophosphamide and lomustine) versus cis-platinum and etoposide in the treatment of advanced non-small cell lung cancer.

From June, 1982 to December, 1984, 35 consecutive patients with histologically proven non-small cell lung cancer (NSCLC) were treated either with methotrexate, adriamycin, cyclophosphamide and CCNU (MACC regimen) or cis-platinum and etoposide (DDP-VP16). The rates of objective responses were, respectively, 15% (3 partial responses out of 20 patients) and 13 (2 out of 15). Times to progression were significantly prolonged in the DDP-VP16 group (median: 29 weeks vs 11), with a trend to improvement in the median survival time (30 weeks vs. 17, P less than 0.1). Except for life-threatening leukopenia in 15% of the MACC patients and intractable vomiting in 47% of patients on cis-platinum based chemotherapy, no serious toxicity was observed. The DDP-VP16 combination seems to be more effective, but less well tolerated, than the MACC regimen and can be recommended for compliant patients with good prognostic factors.

Adult↗