Dataset Information

Tissue specificity of in vitro drug sensitivity.

ABSTRACT: Objectives:We sought to investigate the tissue specificity of drug sensitivities in large-scale pharmacological studies and compare these associations to those found in drug clinical indications. Materials and Methods:We leveraged the curated cell line response data from PharmacoGx and applied an enrichment algorithm on drug sensitivity values' area under the drug dose-response curves (AUCs) with and without adjustment for general level of drug sensitivity. Results:We observed tissue specificity in 63% of tested drugs, with 8% of total interactions deemed significant (false discovery rate <0.05). By restricting the drug-tissue interactions to those with AUC?>?0.2, we found that in 52% of interactions, the tissue was predictive of drug sensitivity (concordance index?>?0.65). When compared with clinical indications, the observed overlap was weak (Matthew correlation coefficient, MCC?=?0.0003, P?>?.10). Discussion:While drugs exhibit significant tissue specificity in vitro, there is little overlap with clinical indications. This can be attributed to factors such as underlying biological differences between in vitro models and patient tumors, or the inability of tissue-specific drugs to bring additional benefits beyond gold standard treatments during clinical trials. Conclusion:Our meta-analysis of pan-cancer drug screening datasets indicates that most tested drugs exhibit tissue-specific sensitivities in a large panel of cancer cell lines. However, the observed preclinical results do not translate to the clinical setting. Our results suggest that additional research into showing parallels between preclinical and clinical data is required to increase the translational potential of in vitro drug screening.

SUBMITTER: Yao F

PROVIDER: S-EPMC6381764 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tissue specificity of in vitro drug sensitivity.

Yao Fupan F Madani Tonekaboni Seyed Ali SA Safikhani Zhaleh Z Smirnov Petr P El-Hachem Nehme N Freeman Mark M Manem Venkata Satya Kumar VSK Haibe-Kains Benjamin B

Journal of the American Medical Informatics Association : JAMIA 20180201 2

<h4>Objectives</h4>We sought to investigate the tissue specificity of drug sensitivities in large-scale pharmacological studies and compare these associations to those found in drug clinical indications.<h4>Materials and methods</h4>We leveraged the curated cell line response data from PharmacoGx and applied an enrichment algorithm on drug sensitivity values' area under the drug dose-response curves (AUCs) with and without adjustment for general level of drug sensitivity.<h4>Results</h4>We obser ...[more]

PMID: 29016819

Similar Datasets

Project description:BackgroundThe screening of lead compounds against in vitro parasite cultures is an essential step in the development of novel anti-malarial drugs, but currently relies on laboratory parasite lines established in vitro during the last century. This study sought to establish in continuous culture a series of recent Plasmodium falciparum isolates to represent the current parasite populations in Africa, all of which are now exposed to artemisinin combination therapy.MethodsPre-treatment P. falciparum isolates were obtained in EDTA, and placed into continuous culture after sampling of DNA. One post-treatment blood sample was also collected for each donor to monitor parasite clonality during clearance in vivo. IC?? estimates were obtained for 11 anti-malarial compounds for each established parasite line, clonal multiplicity measured in vivo and in vitro, and polymorphic sites implicated in parasite sensitivity to drugs were investigated at the pfmdr1, pfcrt, pfdhfr, pfdhps and pfap2mu loci before and after treatment, and in the cultured lines.ResultsPlasmodium falciparum isolates from seven malaria patients with recent travel to three West African and two East African countries were successfully established in long-term culture. One of these, HL1211, was from a patient with recrudescent parasitaemia 14 days after a full course of artemether-lumefantrine. All established culture lines were shown to be polyclonal, reflecting the in vivo isolates from which they were derived, and at least two lines reliably produce gametocytes in vitro. Two lines displayed high chloroquine IC?? estimates, and carried the CVIET haplotype at codons 72-76, whereas the remaining five lines carried the CVMNK haplotype and were sensitive in vitro. All were sensitive to the endoperoxides dihydroartemisinin and OZ277, but IC?? estimates for lumefantrine varied, with the least sensitive parasites carrying pfmdr1 alleles encoding Asn at codon 86.ConclusionsThis study describes the establishment in continuous culture, in vitro drug sensitivity testing and molecular characterization of a series of multiclonal P. falciparum isolates taken directly from UK malaria patients following recent travel to various malaria-endemic countries in Africa. These "HL" isolates are available as an open resource for studies of drug response, antigenic diversity and other aspects of parasite biology.

Dataset Information

Tissue specificity of in vitro drug sensitivity.

Publications

Tissue specificity of in vitro drug sensitivity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure