In vitro testing of chemotherapeutic drug combinations in acute myelocytic leukaemia using the fluorometric microculture cytotoxicity assay (FMCA)

Larsson, Rolf; Fridborg, H; Kristensen, Jörgen; Sundström, Christer; Nygren, Peter

doi:10.1038/bjc.1993.178

Cited by 35 publications

(25 citation statements)

References 18 publications

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“…In previous studies we employed an arbitrarily defined cut-off value (30% SI) for distinguishing sensitive from resistant tumor samples Larsson et al, 1993). In the present study, we employed the median as a cut-off for categorizing the in vitro outcome and for exploring an in vitro drug resistance phenotype referred to as EDR.…”

Section: Discussionmentioning

confidence: 99%

In vitro determination of cytotoxic drug response in ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA)

et al. 1997

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The fluorometric microculture cytotoxicity assay (FMCA), a short‐term in vitro assay based on the concept of total tumor cell kill, was used for testing the cytotoxic drug sensitivity of tumor cells from patients with ovarian carcinoma. A total of 125 fresh specimens was obtained, 98 (78%) of which were analyzed successfully. Data from 45 patients were available for clinical correlations. The FMCA appeared to yield clinically relevant cytotoxic drug sensitivity data for ovarian carcinoma as indicated by a comparison with tumor samples obtained from patients with non‐Hodgkin's lymphoma or kidney carcinoma. Considering the most active single agent in vitro actually given in vivo, and using the median drug activity among all ovarian carcinoma samples as a cut‐off, the sensitivity of the assay and its specificity were 75 and 52%, respectively. Cross‐resistance in vitro was frequently observed between standard drugs but not between standard drugs and Taxol. Ten percent of the specimens showed an extreme resistance for at least 4 of 6 of the drugs investigated. Int. J. Cancer 72:1008–1012, 1997. © 1997 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

In vitro determination of cytotoxic drug response in ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA)

et al. 1997

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“…Compared with previously published approaches, the ISM approach presented here has distinct differences. First, our studies focused on targeted drugs, whereas most of the previous efforts of ex vivo drug testing have focused on conventional chemotherapeutics (23)(24)(25)(26)(27). The ex vivo responses to these agents are often nonselective and more diffi cult to interpret and translate to clinical patient care.…”

Section: Research Articlementioning

confidence: 99%

Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

et al. 2013

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We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profi ling and ex vivo drug sensitivity and resistance testing (DSRT) of patients' cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered fi ve major taxonomic drug-response subtypes based on DSRT profi les, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3 -ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. After progression under DSRT-guided therapies, AML cells displayed signifi cant clonal evolution and novel genomic changes potentially explaining resistance, whereas ex vivo DSRT data showed resistance to the clinically applied drugs and new vulnerabilities to previously ineffective drugs. SIGNIFICANCE:Here, we demonstrate an ISM strategy to optimize safe and effective personalized cancer therapies for individual patients as well as to understand and predict disease evolution and the next line of therapy. This approach could facilitate systematic drug repositioning of approved targeted drugs as well as help to prioritize and de-risk emerging drugs for clinical testing.

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“…If the observed SF after combined treatment (SF obs ) was lower than the SF after treatment with only radiation (SF rad ), SF obs < SF rad , the response was defined as radiosensitizing. Synergistic/sub-additive/antagonistic interactions were analysed, with Student's t-test, using a version of the 'additive model' where the SF after treatments of drug and radiation alone were multiplied to each other to form an 'expected value' of additive SF (SF exp.add ) (30,33). When the observed SF after combined treatment was significantly lower than the expected additive SF, SF obs < SF exp.add , the response was defined as synergistic.…”

Section: Mutation Analyses Of Kras and Brafmentioning

confidence: 99%

The effect of a dimeric Affibody molecule (ZEGFR:1907)2 targeting EGFR in combination with radiation in colon cancer cell lines

et al. 2011

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Abstract. The epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal cancer and is therefore an attractive target for treatment. (Z EGFR:1907 ) 2 is a newly developed dimeric affibody molecule with high affinity to the extracellular part of EGFR. In this study, we evaluated the cytotoxic effects of (Z EGFR:1907 ) 2 in combination with external radiation and the possible inhibitory effects in the EGFR signalling pathways in the colon cancer cell lines HT-29 and HCT116. The effects were compared with an EGFR antibody (cetuximab) and the tyrosine kinase inhibitors (erlotinib and sunitinib). These cell lines are genotypically different with respect to e.g. KRAS and BRAF mutational status, recently shown to be of clinical significance for therapeutic effects. Both cell lines express approximately 100,000-150,000 EGFRs per cell but differ in the radiation response (HCT116, SF2=0.28 and HT-29, SF2=0.70). Exposure to (Z EGFR:1907 ) 2 produced a small, but significant, reduction in survival in HCT116 but did not affect HT-29 cells. Similar results were obtained after exposure to EGF and the EGFR antibody cetuximab. The EGFR tyrosine kinase targeting inhibitor erlotinib and the multi-tyrosine kinase inhibitor sunitinib reduced survival in both cell lines. However, none of the drugs had any significant radiosensitizing effects in combination with radiation. Akt and Erk are central proteins in the EGFR downstream signalling and in the cellular response to ionizing radiation. The activation of Akt (Ser 473) and Erk (Thr202/ Tyr204) by radiation was both dose-and time-dependent. However the activation of EGFR was not clearly affected by radiation. Neither (Z EGFR:1907 ) 2 nor any of the other drugs were able to completely inactivate Akt or Erk. On the contrary, erlotinib stimulated Akt phosphorylation in both cell lines and in HCT116 cells Erk was activated. Overall the results illustrate the complexity in response to radiation and drugs in cells with differential phenotypic status.

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In vitro testing of chemotherapeutic drug combinations in acute myelocytic leukaemia using the fluorometric microculture cytotoxicity assay (FMCA)

Abstract: Summary The fluorometric microculture cytotoxicity assay (FMCA)

Cited by 35 publications

References 18 publications

In vitro determination of cytotoxic drug response in ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA)

In vitro determination of cytotoxic drug response in ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA)

Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

The effect of a dimeric Affibody molecule (ZEGFR:1907)2 targeting EGFR in combination with radiation in colon cancer cell lines

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