FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3102034163> ?p ?o ?g. }

• W3102034163 endingPage "3191" @default.
• W3102034163 startingPage "3191" @default.
• W3102034163 abstract "3191 Reducing the toxicity associated with anticancer drugs is a major challenge that might be overcome by effective drug targeting to the tumour. Antifolates such as raltitrexed and pemetrexed are not specifically tumour targeted because they are transported into cells via the ubiquitously expressed, reduced-folate carrier (RFC). The α-FR is a surface receptor overexpressed in many tumours, particularly ovarian carcinomas. However, expression in normal tissues is relatively low and restricted to some luminal surfaces and therefore not accessible to agents within the circulatory system. Exploiting this knowledge we developed BGC 945, a cyclopenta[g]quinazoline with high affinities for α-FR (Kd ~0.1nM) and TS (Ki = 1.2nM), very low affinity for the RFC (Km ~2mM) and high potency in cultured tumour cells expressing α-FR (IC50 = 1-300nM; dependent on expression level). That BGC 945 transport is FR-mediated is demonstrated by low potency for α-FR negative cells (IC50 ~5µM) and studies in KB tumour-bearing mice demonstrating tumour localisation and selective tumour TS inhibition (Gibbs et al, Cancer Res. 2005). We now describe more detailed preclinical PK and toxicity data from canine studies, and further PD in IGROV-1 ovarian tumour-bearing mice. Unlike rodents, dogs are a clinically relevant toxicity model for TS inhibitors because their plasma thymidine levels are much lower than rodents and more similar to humans. Plasma and tumour deoxyuridine (dUrd) (PD marker of TS inhibition in proliferating tissues and tumour respectively) were measured by HPLC, and plasma BGC 945 by LC-MS/MS. In dogs, the Cmax after 100mg/kg was 621nmoles/ml, 2-fold higher than observed in mice. The AUC INF (1584 hr x nmole/ml) was 10-fold higher in dogs than mice. In vitro experiments with IGROV-1 cells predicted a target drug exposure in vivo for 72h of at least 100nM (or lower concentrations for longer) but not higher than 5µM. Comparison of 100mg/kg dose in mice and dogs led to time above this 100nM threshold of ~14h and >24h respectively (48h ~50nM). Despite the rapid clearance in mice, 100mg/kg induced a rise in dUrd in the IGROV-1 xenograft that was greater than 10-fold for ~48h. Thereafter levels fell but had not returned to pre-treatment levels at 72hr. Plasma dUrd was unchanged over 72h. This prolonged tumour-specific TS inhibition in mice is consistent with the rapid distribution of BGC 945 observed to the tumour and the long half-life in tumour (28h) compared with other tissues. This suggests that the target plasma threshold may be even lower than predicted from the in vitro studies. Despite the higher drug exposure observed in dogs compared with mice at 100mg/kg, no toxicity was observed at this dose and the MTD was ~600mg/kg (gut toxicity). These data suggest that BGC 945 will have the desired tumour targeted profile with minimal toxicities at effective doses." @default.
• W3102034163 created "2020-11-23" @default.
• W3102034163 creator A5016745584 @default.
• W3102034163 creator A5016775053 @default.
• W3102034163 creator A5025928080 @default.
• W3102034163 creator A5037692423 @default.
• W3102034163 creator A5046536911 @default.
• W3102034163 creator A5059545579 @default.
• W3102034163 creator A5080195917 @default.
• W3102034163 creator A5089603827 @default.
• W3102034163 date "2007-05-01" @default.
• W3102034163 modified "2023-09-23" @default.
• W3102034163 title "Preclinical pharmacokinetics (PK) and pharmacodynamics (PD) of BGC 945: a unique tumour targeted thymidylate synthase (TS) by virtue of its selective uptake by the folate receptor (FR)" @default.
• W3102034163 hasPublicationYear "2007" @default.
• W3102034163 type Work @default.
• W3102034163 sameAs 3102034163 @default.
• W3102034163 citedByCount "0" @default.
• W3102034163 crossrefType "journal-article" @default.
• W3102034163 hasAuthorship W3102034163A5016745584 @default.
• W3102034163 hasAuthorship W3102034163A5016775053 @default.
• W3102034163 hasAuthorship W3102034163A5025928080 @default.
• W3102034163 hasAuthorship W3102034163A5037692423 @default.
• W3102034163 hasAuthorship W3102034163A5046536911 @default.
• W3102034163 hasAuthorship W3102034163A5059545579 @default.
• W3102034163 hasAuthorship W3102034163A5080195917 @default.
• W3102034163 hasAuthorship W3102034163A5089603827 @default.
• W3102034163 hasConcept C112705442 @default.
• W3102034163 hasConcept C121608353 @default.
• W3102034163 hasConcept C123321153 @default.
• W3102034163 hasConcept C126322002 @default.
• W3102034163 hasConcept C178790620 @default.
• W3102034163 hasConcept C185592680 @default.
• W3102034163 hasConcept C202751555 @default.
• W3102034163 hasConcept C2778397455 @default.
• W3102034163 hasConcept C2779268555 @default.
• W3102034163 hasConcept C2780306303 @default.
• W3102034163 hasConcept C2780427987 @default.
• W3102034163 hasConcept C2780456651 @default.
• W3102034163 hasConcept C2781382166 @default.
• W3102034163 hasConcept C29730261 @default.
• W3102034163 hasConcept C502942594 @default.
• W3102034163 hasConcept C55493867 @default.
• W3102034163 hasConcept C57992300 @default.
• W3102034163 hasConcept C71924100 @default.
• W3102034163 hasConcept C86803240 @default.
• W3102034163 hasConcept C96232424 @default.
• W3102034163 hasConcept C98274493 @default.
• W3102034163 hasConceptScore W3102034163C112705442 @default.
• W3102034163 hasConceptScore W3102034163C121608353 @default.
• W3102034163 hasConceptScore W3102034163C123321153 @default.
• W3102034163 hasConceptScore W3102034163C126322002 @default.
• W3102034163 hasConceptScore W3102034163C178790620 @default.
• W3102034163 hasConceptScore W3102034163C185592680 @default.
• W3102034163 hasConceptScore W3102034163C202751555 @default.
• W3102034163 hasConceptScore W3102034163C2778397455 @default.
• W3102034163 hasConceptScore W3102034163C2779268555 @default.
• W3102034163 hasConceptScore W3102034163C2780306303 @default.
• W3102034163 hasConceptScore W3102034163C2780427987 @default.
• W3102034163 hasConceptScore W3102034163C2780456651 @default.
• W3102034163 hasConceptScore W3102034163C2781382166 @default.
• W3102034163 hasConceptScore W3102034163C29730261 @default.
• W3102034163 hasConceptScore W3102034163C502942594 @default.
• W3102034163 hasConceptScore W3102034163C55493867 @default.
• W3102034163 hasConceptScore W3102034163C57992300 @default.
• W3102034163 hasConceptScore W3102034163C71924100 @default.
• W3102034163 hasConceptScore W3102034163C86803240 @default.
• W3102034163 hasConceptScore W3102034163C96232424 @default.
• W3102034163 hasConceptScore W3102034163C98274493 @default.
• W3102034163 hasLocation W31020341631 @default.
• W3102034163 hasOpenAccess W3102034163 @default.
• W3102034163 hasPrimaryLocation W31020341631 @default.
• W3102034163 hasRelatedWork W1545998870 @default.
• W3102034163 hasRelatedWork W1567591360 @default.
• W3102034163 hasRelatedWork W1595346903 @default.
• W3102034163 hasRelatedWork W1969739293 @default.
• W3102034163 hasRelatedWork W1988659476 @default.
• W3102034163 hasRelatedWork W2010857122 @default.
• W3102034163 hasRelatedWork W2029925637 @default.
• W3102034163 hasRelatedWork W2045285546 @default.
• W3102034163 hasRelatedWork W2064250310 @default.
• W3102034163 hasRelatedWork W2075287020 @default.
• W3102034163 hasRelatedWork W2079601086 @default.
• W3102034163 hasRelatedWork W2324594876 @default.
• W3102034163 hasRelatedWork W2419053465 @default.
• W3102034163 hasRelatedWork W2568488427 @default.
• W3102034163 hasRelatedWork W2600413252 @default.
• W3102034163 hasRelatedWork W2939059579 @default.
• W3102034163 hasRelatedWork W337105721 @default.
• W3102034163 hasRelatedWork W85287809 @default.
• W3102034163 hasRelatedWork W2438117822 @default.
• W3102034163 hasRelatedWork W2465404375 @default.
• W3102034163 hasVolume "67" @default.
• W3102034163 isParatext "false" @default.
• W3102034163 isRetracted "false" @default.
• W3102034163 magId "3102034163" @default.
• W3102034163 workType "article" @default.