Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: a Phase I study.

BACKGROUND: DTS-108 is a hydrosoluble prodrug, where the SN-38 moiety is covalently linked to a 20-amino acid vector peptide by a specific esterase-sensitive cross-linker, releasing 7-ethyl-10-hydroxycampthotecin (SN-38) by esterase bond cleavage. METHODS: The pharmacokinetics of DTS-108, adverse events graded according to NCI-CTCv3.1, dose-limiting toxicities at cycle 1, the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of intravenous DTS-108 (1-2 hours) every 2 weeks were evaluated in a first-in-human Phase I study in patients with advanced/metastatic carcinomas, according to an accelerated dose escalation design. SN-38 and SN-38 glucuronide (SN-38G) levels were evaluated with fluorescence high-performance liquid chromatography (HPLC) test, then liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods. RESULTS: Forty-two patients received DTS-108 across 14 dosing cohorts (range 3-416 mg/m2). At 416 mg/m2, three out of six patients had grade 4 neutropenia thereby defining the MTD and the RP2D at 313 mg/m2. Fluorescence HPLC was inaccurate to quantify DTS-108 and its metabolites (SN-38 and SN-38G). New processes and analytical LC/MS/MS methods for testing SN-38 were implemented. At a dose of 313 mg/m2, mean DTS-108, SN-38, and SN-38G area under the plasma concentration-time curve to infinity (coefficients of variation %) were 439,293 (24%), 1,992 (34%), and 4,538 (46%) h·ng/mL. Stable disease (according to Response Evaluation Criteria in Solid Tumors) was observed in nine patients. CONCLUSION: Assessing SN-38 concentration using fluorescence HPLC is questionable since this method failed to monitor dose escalation of DTS-108, a new topoisomerase I inhibitor, due to ex vivo degradation. LC/MS/MS methods were consistent in evaluating SN-38 exposures allowing drug monitoring. The maximum tolerated dose of DTS-108 was 416 mg/m2. The RP2D for intravenous DTS-108 was 313 mg/m2 every 2 weeks in patients with advanced/metastatic solid tumors.

Chromosome size variation occurs in cloned Plasmodium falciparum on in vitro cultivation

Variaçöes de tamanho nos cromossomos de linhagens de parasitos derivados de um clone de Plasmodium falciparum. Tais variaçöes desenvolveram-se durante períodos de muitos meses em parasitos haplóides na fase eritrocitária, mantidos in vitro. As variaçöes foram mais numerosas em populaçöes com resistência à mefloquina, induzida pelo cultivo sob pressäo de droga, do que em parasitas controles mantidos em meio de cultura sem droga. Em alguns casos, as modificaçöes de tamanho foram täo grandes que alteraram a ordem relativa das bandas de DNA cromossômico em separaçöes através de eletroforese em gel de "pulsed-field gradient". As regiöes subteloméricas dos cromossomos säo especialmente ativas, estando envolvidas em rearranjos responsáveis pelas alteraçöes de tamanho. O papel biológico destes rearrranjos näo é conhecido. Entretanto, sua ocorrência em experimentos controles, bem como sua frequente apariçäo em condiçöes de pressäo por mefloquina, sugerem que tais rearranjos reflititiam modificaçöes generalizadas da estrutura genômica em resposta às condiçöes ambientais