Busulphan is active against neuroblastoma and medulloblastoma xenografts in athymic mice at clinically achievable plasma drug concentrations

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 μg h ml−1) was close to the mean total systemic exposure in children receiving high-dose busulphan (102.4 μg 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. 1999 Cancer Research Campaig

Market access to new anticancer medicines for children and adolescents with cancer in Europe

BACKGROUND AND AIMS: There is an alarming delay in Europe for anticancer medicines becoming accessible for children. Following a paediatric European Union marketing authorisation, national Health Technology Assessment (HTA) agencies evaluate effectiveness, and safety of medicines to support decision on their cost and reimbursement. This study (a SIOPE Access to Medicines project) aimed to evaluate how these HTA evaluations take place for anticancer medicines indicated for paediatric use in Europe and to explore where the delays for market access originate. METHODS: We obtained HTA reports from the public domain for nine European countries for blinatumomab, dinutuximab beta and tisagenlecleucel. We evaluated the time elapsed between marketing authorisation for a paediatric indication and a national HTA decision and the nature of the decision. RESULTS: Out of 23 HTA decisions (four countries without blinatumomab report), 18 were positive, two with restrictions, three negative. For blinatumomab, tisagenlecleucel and dinutuximab beta, the median time to an HTA decision after regulatory approval for paediatric use was 353 days (range 193-751), 141 days (range 77-517) and 515 days (range 0-780), respectively, with variability between countries. Dinutuximab beta and tisagenlecleucel were first introduced in children, but did not result in shorter time to HTA decision. For blinatumomab, marketing authorisation followed 1008 days after the indication in adults, with HTA applications submitted a median of 167 days later, and a recommendation after 145 days. CONCLUSIONS: This study reveals ample variability in HTA decision making in nine European Union countries. Collaboration and alignment of required evidence is needed to facilitate robust scientific HTA assessments, also considering methodological challenges in paediatric oncology

Potential of sorghum and physic nut (Jatropha curcas) for management of plant bugs (Hemiptera: Miridae) and cotton bollworm (Helicoverpa armigera) on cotton in an assisted trap-cropping strategy

The cotton bollworm (CBW) Helicoverpa armigera and to a lesser extent plant bugs (PB) (Hemiptera: Miridae) are important pests of cotton in Africa. For sustainability reasons, it is necessary to reduce use of chemical control measures for these pests. A promising alternative to chemical control of both CBW and PB is trap cropping, assisted with botanical pesticides sprays, if needed. We report studies conducted from 1995–98 on sorghum attractiveness to PB and CBW, on the potential of physic nut (Jatropha curcas) extracts [particularly the phorbol ester (PE) fraction of the oil] for sorghum protection fromPB damage, and on the insecticidal activity of Jatropha extracts on CBW. At the ICRISAT research station (Samanko, Mali), infestation by the five main species of PB (accounting for 96% of total) was much higher on sorghum than on cotton. In the Kolokani region, CBW infestation was negligible on the Guinea loose-panicled sorghum cultivar Bibalawili, while it was significant on both compact-panicled PB susceptible ICSH 89002 and PB resistant Malisor 84-7. At Samanko, Jatropha oil application on sorghum panicles showed some effect on PB when damage level was high, better than Jatropha and neem aqueous extracts. However, it did not compete with pyrethroid protection level. PE contact toxicity on CBW larvae was too low to determine a LC 50. Aningestion insecticidal activity of PE was found on all tested larval instars. Contact toxicity LC 50 of PE on eggs was 1.66 g ml-1. Development of larvae and reproductive ability of adults derived from new-laid eggs treated with solutions of 0.35 g ml-1 PE and above were considerably affected. Prospects for using sorghum and Jatropha extracts for cotton protection against insect pests in an assisted trap-cropping strategy are discussed

No topoisomerase I alteration in a neuroblastoma model with in vivo acquired resistance to irinotecan

CPT-11 (irinotecan) is a DNA-topoisomerase I inhibitor with preclinical activity against neuroblastoma (NB) xenografts. The aim was to establish in vivo an NB xenograft resistant to CPT-11 in order to study the resistance mechanisms acquired in a therapeutic setting. IGR-NB8 is an immature NB xenograft with MYCN amplification and 1p deletion, which is sensitive to CPT-11. Athymic mice bearing advanced-stage subcutaneous tumours were treated with CPT-11 (27 mg kg−1 day−1 × 5) every 21 days (1 cycle) for a maximum of four cycles. After tumour regrowth, a new in vivo passage was performed and the CPT-11 treatment was repeated. After the third passage, a resistant xenograft was obtained (IGRNB8-R). The tumour growth delay (TGD) was reduced from 115 at passage 1 to 40 at passage 4 and no complete or partial regression was observed. After further exposure to the drug, up to 28 passages, the resistant xenograft was definitively established with a TGD from 17 at passage 28. Resistant tumours reverted to sensitive tumours after 15 passages without treatment. IGR-NB8-R remained sensitive to cyclophosphamide and cisplatin and cross-resistance was observed with the topoisomerase I inhibitor topotecan. No quantitative or qualitative topoisomerase I modifications were observed. The level of expression of multidrug resistance 1 (MDR1), MDR-associated protein 1 (MRP1) and, breast cancer resistance protein, three members of the ATP-binding cassette transporter family was not modified over passages. Our results suggest a novel resistance mechanism, probably not involving the mechanisms usually observed in vitro

The Search Coil Magnetometer for THEMIS

International audienceTHEMIS instruments incorporate a tri-axial Search Coil Magnetometer (SCM) designed to measure the magnetic components of waves associated with substorm breakup and expansion. The three search coil antennas cover the same frequency bandwidth, from 0.1 Hz to 4 kHz, in the ULF/ELF frequency range. They extend, with appropriate Noise Equivalent Magnetic Induction (NEMI) and sufficient overlap, the measurements of the fluxgate magnetometers. The NEMI of the searchcoil antennas and associated pre-amplifiers is smaller than 0.76 pT/ p Hz at 10 Hz.The analog signals produced by the searchcoils and associated preamplifiers are digitized and processed inside the IDPU, together with data from the EFI instrument. Searchcoil telemetry includes waveform transmission, FFT processed data, and data from a filter bank. The frequency range covered in waveform depends on the available telemetry. The searchcoils and their three axis structures have been precisely calibrated in a quiet site, and the calibration of the transfer function is checked on board usually once per orbit. The tri-axial searchcoils implemented on the five THEMIS spacecraft are working nominally

Phase I trial and pharmacological study of a 3-hour paclitaxel infusion in children with refractory solid tumours: a SFOP study

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m2). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity. © 2001 Cancer Research Campaign http://www.bjcancer.co