orabase and Neuroblastoma

High-dose busulphan-containing chemotherapy regimens have shown high response rates in children with relapsed or refractory neuroblastoma, Ewing's sarcoma and medulloblastoma. However, the anti-tumour activity of busulfan as a single agent remains to be defined, and this was evaluated in athymic mice bearing advanced stage subcutaneous paediatric solid tumour xenografts. Because busulphan is highly insoluble in water, the use of several vehicles for enteral and parenteral administration was first investigated in terms of pharmacokinetics and toxicity. The highest bioavailability was obtained with busulphan in DMSO administered i.p. When busulphan was suspended in carboxymethylcellulose and given orally or i.p., the bioavailability was poor. Then, in the therapeutic experiments, busulphan in DMSO was administered i.p. on days 0 and 4. At the maximum tolerated total dose (50 mg kg(-1)), busulphan induced a significant tumour growth delay, ranging from 12 to 34 days in the three neuroblastomas evaluated and in one out of three medulloblastomas. At a dose level above the maximum tolerated dose, busulphan induced complete and partial tumour regressions. Busulphan was inactive in a peripheral primitive neuroectodermal tumour (PNET) xenograft. When busulphan pharmacokinetics in mice and humans were considered, the estimated systemic exposure at the therapeutically active dose in mice (113 microg h ml(-1)) was close to the mean total systemic exposure in children receiving high-dose busulphan (102.4 microg h ml(-1)). In conclusion, busulphan displayed a significant anti-tumour activity in neuroblastoma and medulloblastoma xenografts at plasma drug concentrations which can be achieved clinically in children receiving high-dose busulphan-containing regimens.

Topics: Administration, Oral; Animals; Biological Availability; Brain Neoplasms; Busulfan; Carboxymethylcellulose Sodium; Dimethyl Sulfoxide; Female; Humans; Injections, Intraperitoneal; Medulloblastoma; Mice; Mice, Nude; Neuroblastoma; Neuroectodermal Tumors, Primitive; Solubility; Transplantation, Heterologous; Tumor Cells, Cultured

Therapeutic efficacy and toxicity were evaluated in 28 children with acute lymphoblastic leukemia, in ten with acute nonlymphoblastic leukemia (ANLL), and in 13 with metastatic neuroblastoma. All were refractory to standard chemotherapeutic agents and 25 were refractory to an investigational drug. The initial dose was 12 mg/m2/day and was based on an established maximal dose tolerated in adults. This dose was found to be intolerable in 5 of 5 children with leukemia. Similarly an initial dose of 9 mg/m2/day was intolerable in 4 of 5 patients with leukemia. The starting dose in the next 28 children with leukemia or neuroblastoma was 3 mg/m2. This drug was gradually increased to the highest tolerated dose by 3-mg/m2 increments. Fifteen children with acute lymphoblastic leukemia, 3 children with ANLL, and 2 children with neuroblastoma received the drug daily. Seven patients with ANLL and 7 patients with neuroblastoma received the drug biweekly. Seventeen patients with acute lymphoblastic leukemia, 6 patients with ANLL, and 5 patients with neuroblastoma had an adequate trial of the drug. An adequate trial was defined as a minimum of 5 weeks of therapy unless progressive disease developed. Side effects of the drug were striking and included fever, hypotension, myalgia, bone pain, arthralgia, arthritis, abdominal pain, liver toxicity, thrombocytopenia, and neurotoxicity. No complete remission occurred although interferon levels above 100 units/ml were induced in nearly 50% of the patients.

Topics: Acute Disease; Adolescent; Carboxymethylcellulose Sodium; Child; Child, Preschool; Drug Evaluation; Humans; Interferon Inducers; Interferons; Leukemia; Methylcellulose; Neuroblastoma; Poly I-C; Polylysine

A Phase II study of poly(I,C)-LC was performed in 28 children and adolescents with acute lymphoblastic leukemia (ALL), 10 with acute nonlymphoblastic leukemia (ANLL), and 13 with metastatic neuroblastoma. All were refractory to standard chemotherapeutic agents and 25 to an investigational drug. Initial doses of 12 mg/m2 and 9 mg/m2 were intolerable. However, 9 mg/m2 was tolerable in the majority of patients when the drug was started at 3 mg/m2 and increased by 3 mg/m2 increments. Fifteen children with ALL, three with ANLL, and two with neuroblastoma received the drug daily. Seven patients with ANLL and seven children with neuroblastoma received the drug biweekly. Twenty-eight patients received an adequate trial, which was defined as a minimum of 5 weeks at the maximal tolerated dose, unless there was progressive disease at the maximal tolerated dose. Side effects of the drug were striking, and included fever, hypotension, myalgia, bone pain, arthralgia, arthritis, abdominal pain, liver toxicity, thrombocytopenia, and neurotoxicity. No complete remissions occurred in spite of interferon levels above 100 U in nearly 50% of patients.

Topics: Acute Disease; Carboxymethylcellulose Sodium; Child; Drug Evaluation; Female; Humans; Interferon Inducers; Interferons; Leukemia; Leukemia, Lymphoid; Male; Methylcellulose; Neuroblastoma; Poly I-C; Polylysine

The addition of 1% (w/v) carboxymethyl cellulose to the culture medium induces the formation of neurites of clone N18 neuroblastoma cells even in the presence of normal (5-10%) serum supplement concentrations, which rivals that previously observed by growth in low 0.1% serum. Heavy metal ions associated with the carboxymethyl cellulose were responsible for small increases in the sizes of cell bodies during treatment. Pretreatment of the PC12 pheochromocytoma line of neuroblasts with carboxymethyl cellulose for 1 day prior to their stimulation with nerve growth factor resulted in an acceleration in the rate, but not extent, of neurite outgrowth.

Topics: Animals; Carboxymethylcellulose Sodium; Cell Differentiation; Cell Line; Copper; Drug Interactions; Ferrous Compounds; Methylcellulose; Mice; Neuroblastoma; Neurons; Pheochromocytoma; Zinc