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PubMed1984

Cytophotometry of nucleic acids and morphometry of motor neurons and oligodendroglia in the spinal cord of rats treated with CCNU (lomustine).

CCNU, a nitrosourea derivative, is a potent agent used in cancer chemotherapy and effective also in therapy of brain tumors. This cytostatic is considered to be free of neurotoxic effects. To establish the influence of CCNU on the central nervous system, the drug was administered in oil suspension, intragastrically, to adult rats. The animals received four doses of the drug in 7 days intervals, including three doses of 2.5 mg and the fourth of 5.0 mg. On the 7th day after the last dose experimental rats were sacrificed, their spinal cord removed, fixed in Baker's solution and embedded in paraffin. The sections were stained according to Einarson and subjected to Feulgen reaction for morphometric, karyometric and cytophotometric studies. The measurements of motor neurons and oligodendroglia from anterior horns of the cervical, thoracic and lumbar spinal cord were performed with scanning microscope "Morphoquant" coupled to the KSR 4100 computer. CCNU administration lead to morphometric, karyometric and cytophotometric changes in examined cells. The karyometric and cytophotometric changes were statistically significant and more extensive than morphometric changes which were insignificant. Furthermore, CCNU caused a statistically significant decrease of DNA content in motor neurons and oligodendrocytes in all examined parts of the spinal cord.

Animals↗
PubMed1976

Lomustine (CeeNU).

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Brain Neoplasms↗
PubMed2006

Re-evaluation of the cost effectiveness of temozolomide for malignant gliomas in British Columbia.

STUDY OBJECTIVES: To re-evaluate the cost effectiveness and median overall survival (OS) achieved in patients with recurrent malignant gliomas treated with temozolomide in British Columbia, as compared to previous lomustine use in the same patient population based on updated outcomes data. Results were also compared to temozolomide literature reports. METHODS: A retrospective medical record review was performed to identify patients who received single agent temozolomide or lomustine during successive, prespecified time periods. Data were collected on survival, duration of therapy, drug cost, labour and supplies, and successive or prior chemotherapy. RESULTS: Forty-one patients in the temozolomide group and 25 patients in the lomustine group were analysed. The median OS was 33.3 weeks (95% CI 28.4, 42.1 weeks) and 37.7 weeks (95% CI 25.0, 88.4 weeks) respectively (P = 0.783). Temozolomide patients received a mean of 5.1 cycles of drug treatment, with a mean cost per patient of 10746 dollars (CAD). In contrast, lomustine patients received a mean of 3.3 cycles of therapy, with a mean cost per patient of 129 dollars (CAD). The cost-effectiveness analysis showed that temozolomide was generally not a cost-effective strategy and that lomustine was the dominant strategy. In the sensitivity analysis, in scenarios where median OS was prolonged with temozolomide as compared to lomustine, the incremental cost-effectiveness ratio for each life year gained ranged from 32,247 dollars to 162,186 dollars. CONCLUSION: No difference in survival was observed between patients treated with single agent lomustine and temozolomide. Based on the higher cost and lack of additional clinical benefit of temozolomide, lomustine is a more cost-effective treatment strategy.

Adult↗
PubMed1998

The risk of acute leukemia in patients treated for Hodgkin's disease is significantly higher aft [see bined modality programs than after chemotherapy alone and is correlated with the extent of radiotherapy and type and duration of chemotherapy: a case-control study.

BACKGROUND AND OBJECTIVE: Patients treated for Hodgkin's disease have an increased risk of developing subsequent acute leukemia. This co-operative study was conducted to assess the relative risk associated with several candidate factors including age, splenectomy, combined modality therapy and cumulative drug dose including alkylating agents and nitrosurea derivatives. DESIGN AND METHODS: This study evaluated the risk of acute leukemia according to pretreatment variables and therapy modalities among 1659 patients treated for Hodgkin's disease and followed for a median time of 10 years. Both case-control and actuarial risk studies were performed. Median age was 34 years (range: 12-83); 53% of patients were splenectomized. As to the overall therapy, 348 patients (21%) were given radiotherapy (RT) alone, 375 (23%) chemotherapy (CT) alone (including MOPP, MOPP + ABVD or MOPP + ABVD + lomustine); 936 (56%) received both CT and RT, either as primary or salvage treatment. RESULTS: The overall 15-year actuarial risk of leukemia was 4.2%; the hazard function curve showed two peaks of risk at the 3th and the 8th year from the initiation of therapy and no leukemia beyond the 12th year of follow-up. Risk of leukemia was 0.3% after RT alone, 2.8% after CT alone (2.2% after MOPP; 4.4% after MOPP + ABVD + lomustine), and 5.4% in patients given combined modality therapy (10.2% for RT + MOPP; 15.6% for RT + MOPP + lomustine). No leukemia occurred after ABVD alone and the risk was low (0.6%) when neither mechlorethamine nor lomustine were utilized. Patients who had received extended radiotherapy including abdomen and pelvis in addition to MOPP showed a significantly higher risk of leukemia compared to those given limited RT + MOPP (P = 0.01). Case-control analysis indicated advanced stage, type and duration (> 8 months) of CT and extension of RT as significant risk factors for leukemia. Compared to RT alone, the odds ratio was 5.9 after MOPP + extended RT, and 8 when a lomustine-containing regimen was used, as well. Neither age nor splenectomy were independent risk factors for leukemia; splenectomy was influential only when patients had been given MOPP chemotherapy, as well. INTERPRETATIONS AND CONCLUSIONS: Both case-control and actuarial analyses indicated that: a) combined modality therapy with MOPP and extensive RT (including abdomen and pelvis), and the use of lomustine added to the leukemogenic risk of MOPP alone; b) programs without mechlorethamine, procarbazine and lomustine were almost devoid of leukemogenic risk.

Abdomen↗
PubMed1998

The effects of different antineoplastic agents and of pretreatment by modulators on three melanoma lines.

BACKGROUND: The chemotherapy of melanoma patients must be improved because of the naturally poor response and acquired resistance of this disease. METHODS: The authors used mouse (B16F10) and human (SK-MEL-28 and SK-MEL-1) melanoma lines for in vitro treatment with melphalan, lomustine, fotemustine, and 4-hydroxyanisole (4-HA) alone, combined and after pretreatment with buthionine sulfoximine (BSO), ethacrynic acid (EA), and azelaic acid (AZA). RESULTS: Melphalan was the most effective individual drug, followed by lomustine, fotemustine, and 4-HA. The simultaneous administration of two agents was disappointing, although some combinations slightly improved the response compared with the individual treatments. Pretreatment with BSO enhanced the cytotoxicity of melphalan and lomustine 10-fold in B16F10 and 7.5-fold in SK-MEL-28, increasing the toxicity of fotemustine in all 3 lines. EA potentiated lomustine and fotemustine 9-fold and melphalan 5-fold in B16F10 and SK-MEL-28. AZA increased the effectiveness of lomustine and fotemustine in B16F10 and to a lower degree in the two human lines. 4-HA was the poorest drug for sensitization; only B16F10 BSO followed by 4-HA treatment demonstrated increased toxicity, and all other combinations with 4-HA were negative or antagonistic. There was a strong relationship between dopa oxidase activity and the toxicity of 4-HA. CONCLUSIONS: B16F10 was the most sensitive to all treatments and SK-MEL-1 the most resistant. Melphalan was the most active individual drug and 4-HA the least. Combinations of two drugs did not result in improved activity compared with drugs administered alone. Pretreatment with modulator seems to be a potential method for enhancing some treatments.

Animals↗
PubMed1995

A new preparatory regimen for autologous bone marrow transplantation for patients with lymphoma.

BACKGROUND: This trial studied the feasibility and efficacy of a new preparatory regimen for autologous bone marrow transplantation for patients with advanced lymphoid malignancies. METHODS: Twenty-one patients with Hodgkin's disease (n = 12) and non-Hodgkin's lymphoma (n = 9) were treated in this study. Lomustine was substituted for carmustine) in a dose-escalation study with an initial dose of 6 mg/kg and increasing by 3 mg/kg in groups of four patients. The preparatory regimen consisted of lomustine (6-15 mg/kg) orally on Day -6, etoposide (60 mg/kg) intravenously (i.v.) on Day -4, and cyclophosphamide (100 mg/kg) i.v. on Day -2. Peripheral blood progenitor cells and/or bone marrow were infused on Day 0. RESULTS: Lomustine was well tolerated in all patients with no significant toxicity specific to this drug. Engraftment was prompt: the time to achieving greater than or equal to 500 granulocytes/microliters was 12 days (range, 9-16 days) and the time to achieving greater than or equal to 25,000 platelets/microliters without transfusion support was 16 days (range, 9-22 days). Five patients experienced interstitial pneumonitis, three of whom had active or recent interstitial pneumonitis before bone marrow transplantation, and one who just completed mantle irradiation. Three patients died from this preparatory regimen, one of progressive interstitial pneumonitis, one of Legionella pneumonia, and one of multiorgan failure. Three patients with non-Hodgkin's lymphoma relapsed. Fourteen patients are currently alive and disease free to date. The actuarial are currently alive and disease free to date. The actuarial disease free survival was 57%, with a median follow-up of 23 months (range, 1-48 months). CONCLUSION: The preparatory regimen consisting of lomustine/etoposide/cyclophosphamide is active in treating patients with lymphomas. Further trials with high doses of lomustine are warranted.

Adolescent↗
PubMed1984

Characterization of drug-loaded poly(d,l-lactide) microspheres.

Lomustine and progesterone have been incorporated in biodegradable poly(d,l-lactide) microspheres by evaporating dichloromethane from stirred dichloromethane-in-water emulsions. Spherical microspheres with lomustine or progesterone payloads less than or equal to 23% were obtained. Higher lomustine payloads gave irregularly shaped particles. Microspheres with less than or equal to 68% progesterone were obtained, but free drug crystals formed on the surface of such microspheres. Increased agitation rates decreased mean microsphere size. Addition of drug to the dichloromethane phase increased average particle size relative to that obtained with drug-free microspheres prepared under the same experimental conditions. Complete evaporation of the dichloromethane, while the medium was continuously stirred, promoted formation of free drug crystals in the aqueous phase. Increased emulsifier concentrations did not significantly enhance drug incorporation efficiency within the microspheres. Shelf-life stability of lomustine and progesterone was reduced by incorporation in the microspheres, presumably due to their molecular dispersion in the poly(d,l-lactide).

Crystallization↗
PubMed2002

Modulation of growth and radiochemosensitivity of human malignant glioma cells by acidosis.

BACKGROUND: Glioblastoma commonly is characterized by hypoxia and acidosis and the histologic features of tissue necrosis and neovascularization. Current approaches of adjuvant radiochemotherapy for patients with glioblastoma have only a modest impact on the natural course of this disease. METHODS: The authors examined the effects of acidosis on growth and response to irradiation and chemotherapy in cultured human malignant glioma cells. RESULTS: The authors found that mild acidosis (pH 7.0) inhibited the growth of cell lines that retained wild type p53 activity but did not inhibit the growth of cell lines that were devoid of p53 function. Transfer of a dominant-negative p53 gene into p53 wild type cells failed to override the acidosis-conferred growth arrest, suggesting that loss of p53 activity per se does not mediate escape from acidosis-induced growth inhibition. Moderate acidosis (pH 6.6) inhibited the growth of all cell lines. Acidosis-mediated growth arrest was not associated with a specific type of cell cycle arrest, e.g., in G0/G1 or G2/M phase. Acidosis did not result in consistent changes in radiosensitivity; however, it enhanced the cytotoxic effects of lomustine but conferred protection from topotecan, vincristine, teniposide, and cisplatin cytotoxicity. Lomustine exhibited enhanced stability at low pH, providing a putative mechanism for the enhanced cytotoxic effects of lomustine in acidotic conditions. Decreased sensitivity to the other drugs did not result from altered multidrug resistance drug transport activity. CONCLUSIONS: Taken together, the current results suggest that tissue acidosis may be an important determinant of glioma cell responses to adjuvant radiochemotherapy. The superior activity of nitrosoureas, such as lomustine, compared with other agents in patients with glioblastoma may result in part from prolonged drug stability in an acidotic microenvironment.

Acidosis↗
PubMed1996

Dapsone in prevention of recurrent neutrophilic eccrine hidradenitis.

Neutrophilic eccrine hidradenitis has been described in patients with acute myelogenous leukemia and other malignant diseases, usually during chemotherapy. We describe a 46-year-old man with Hodgkin's disease in whom neutrophilic eccrine hidradenitis developed after each of the first two treatments with lomustine. Dapsone, 100 mg daily, was initiated 48 hours before the patient's third treatment with lomustine and was continued for 14 days. This regimen was successful in suppressing the reaction during the first course and three subsequent courses of lomustine.

Antineoplastic Agents↗