A promising camptothecin derivative: Semisynthesis, antitumor activity and intestinal permeability

Oral administration of camptothecin (Cm) derivatives and other antitumoral agents is being actively developed in order to improve the quality of life of patients with cancer. Though several lipophilic derivatives of CPT have shown interesting oral bioavailability in preclinical and clinical studies, only Topotecan has been approved for this route of administration. Semisynthesis, antitumor activity, biological inhibition mechanism, and in situ intestinal permeability of 9, 10-[1,3]-Dioxinocamptothecin (CDiox), an unexplored CPT derivative, have been studied in this paper. The hexacyclic analog was as effective as Topotecan and CPT in different tumor cell lines, showing an expected similar apoptosis cell mechanism and high ability to inhibit DNA synthesis in HeLa, Caco-2, A375 and MDA-MB-231 cell lines. Furthermore, in vitro and in situ pharmacokinetics transport values obtained for CDiox displayed more favorable absorption profile than CPT and Topotecan. (C) 2014 Elsevier Masson SAS. All rights reserved.G.R.-B. acknowledges Instituto de Tecnologia Quimica for a scholarship; Consolider-Ingenio 2010 (proyecto MULTICAT), Sub-programa de Apoyo a Centros de Excelencia Severo Ochoa, and Agencia de Gestico, d'Ajuts Universiteris i de Recerca (2009 SGR 758, to S.S.) I.G.-A., V.M.-S., M.G.-A. and M. B. acknowledge financial support from the European Financial Commission (Red bioFarma DCI-ALA/19.09.01/10/21526/245-297/ALFA III (2010)). J.L.G.-G. acknowledges the financial support of the CIBERER (Biomedical Network Research Center for Rare Diseases) ISCIII.Rodríguez Berna, G.; Mangas Sanjuan, V.; Gonzalez Alvarez, M.; Gonzalez Álvarez, I.; Garcia Gimenez, JL.; Díaz Cabañas, MJ.; Bermejo, M.... (2014). A promising camptothecin derivative: Semisynthesis, antitumor activity and intestinal permeability. European Journal of Medicinal Chemistry. 83:366-373. doi:10.1016/j.ejmech.2014.06.050S3663738

Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats

Accumbal dopamine (DA) is generally accepted to participate in the neural mechanisms underlying drug dependence. Recently the involvement of accumbal DA in drug-seeking behaviour has gained more experimental attention. To study an involvement of accumbal DA in drug-seeking behaviour within and between daily self-administration behaviour, changes in extracellular DA concentration in the nucleus accumbens (NAc) shell were measured during the daily dynamics of intravenous heroin and cocaine self-administration. Groups of drug naive rats were allowed to intravenously self-administer heroin (30 mug/infusion) and cocaine (30 mug/infusion) during five consecutive daily 3 h sessions. Extracellular DA concentrations in the NAc were measured before and after a single 3 h session (acute) and before and after 5 consecutive 3 h sessions (repeated). Following acute and repeated heroin and cocaine self-administration the extracellular DA concentration in the NAc shell was increased by two-fold to three-fold over baseline. These changes in DA concentrations are thought to reflect a direct effect of heroin and cocaine on DA neurotransmission in the NAC shell. Measurement of basal DA concentrations before the self-administration sessions revealed that just before the scheduled 5th self-administration session the (absolute) basal DA levels in the NAc in heroin or cocaine self-administering animals were decreased by approximately halve, as compared to drug-naive animals. It is assumed that just before a scheduled next session the (daily) desire for the drug is high. This decrease in basal DA neurotransmission in the NAc shell may, therefore, reflect an involvement of accumbal DA in drug-seeking behaviour during daily self-administration behaviour. The results demonstrate that initiation of i.v. heroin and cocaine self-administration is linked with changes in extracellular levels of DA in the NAc shell. Moreover, the present data suggest that accumbal DA might be involved in processes underlying the motivational aspects involved in daily drug-seeking behaviour, and that neuroadaptive changes in the mesolimbic DA system due to repeated drug intake lead to an tonic decrease in overall DA activity in the NAc