ABSTRACT
[This corrects the article DOI: 10.1093/narcan/zcab021.].
ABSTRACT
Topoisomerase inhibitors are potent DNA damaging agents which are widely used in oncology, and they demonstrate robust synergistic tumor cell killing in combination with DNA repair inhibitors, including poly(ADP)-ribose polymerase (PARP) inhibitors. However, their use has been severely limited by the inability to achieve a favorable therapeutic index due to severe systemic toxicities. Antibody-drug conjugates address this issue via antigen-dependent targeting and delivery of their payloads, but this approach requires specific antigens and yet still suffers from off-target toxicities. There is a high unmet need for a more universal tumor targeting technology to broaden the application of cytotoxic payloads. Acidification of the extracellular milieu arises from metabolic adaptions associated with the Warburg effect in cancer. Here we report the development of a pH-sensitive peptide-drug conjugate to deliver the topoisomerase inhibitor, exatecan, selectively to tumors in an antigen-independent manner. Using this approach, we demonstrate potent in vivo cytotoxicity, complete suppression of tumor growth across multiple human tumor models, and synergistic interactions with a PARP inhibitor. These data highlight the identification of a peptide-topoisomerase inhibitor conjugate for cancer therapy that provides a high therapeutic index, and is applicable to all types of human solid tumors in an antigen-independent manner.
ABSTRACT
BACKGROUND: Rates of non-attendance within IAPT are 45-48%. Non-attendance has negative implications for patients, staff and services. AIMS: This research aimed to identify service-related factors that contribute to non-attendance. METHOD: Qualitative interviews with 14 patients recruited from six IAPT services in the South West. These were individuals who, having been referred to IAPT, never attended, or only attended one treatment contact. They were interviewed face-to-face or by telephone using semi-structured interview schedules. The resulting data were analysed thematically through an iterative qualitative analysis using data mapping sheets. RESULTS: Five themes emerged from an analysis of the data including: the waiting process, the relationship between IAPT services and GPs, expectations of assessment and treatment, rigidity of service and practitioner contributions to the relationship. CONCLUSIONS: The analysis identifies ways in which IAPT services could reduce non-attendance. It also highlights areas of interest for future non-attendance in healthcare research, particularly collaborative care and protocolisation of treatment.
