Hi,

The IC50 versus GI50 indices are used as synonyms in the literature, while they are not translating exactly the same features from a biological point of view.

If you are using a colorimetric assay like the MTT popular one or the SRB one used by the NCI, the GI50/IC50 concentration refers to the concentration of the compound of interest that will reduce by 50% the growth of the treated cells as compared to the control ones after 48-72 h (depending on the labs) of culture in the presence of the compound.

As referenced in the instructions for authors of the Journal of Natural Products, a compound which is CYTOTOXIC and whose IC50/GI50 is > 10 µM should be considered as inactive, and this is also the position adopted by the NCI as referenced to you by Marc.

In contrast, if the compound is CYTOSTATIC, the GI50/IC50 "absolute concentration" will not be actually indicative of the anticancer "killing effects".

The attached article from Galluzzi and colleagues (from Guido Kroemer group) comprehensively describes the various cell death types.

We (Kornienko et al., J Med Chem 2013) have accordingly reviewed those compounds that induce the various cell death types described by Galluzzi et al. (2012).

The simple morphological analyses under phase-contrast microscopy while you are culturing your cells will easily indicate you if your compound is rather cytotoxic or rather cytostatic (see the attached articles).

From a more than gross point of view:

* if the morphological analyses clearly indicate cytotoxic effects after 72h of culturing at the GI50 concentration revealed by a colorimetric assay, then you can conclude that the sensitivity of your cell line(s) for your compound of interest ranges between xx and xx µM (depending on the number of cell lines analyzed).

* if cytotoxic, your compound can be considered as:

- highly active if its GI50 is < 1 µM

- active if its GI50 is ranging between 1 and 10 µM,

- inactive if its GI50 is > 10 µM

You can make exactly the same reasoning in terms of the sensitivity (highly sensitive - moderately sensitive - weakly sensitive) if you are taking into account the cut-off values indicated above, but IF and ONLY IF your compound of interest is cytotoxic;

* if the morphological analyses tend to bring you on a "cytostatic conclusion", the story becomes more complicated...

If needed, I am ready to help you on concrete examples generated from your own studies.

Best regards,

Robert

Hi,

I agree that there is some confussion about the different values and sensibility of Celle towards drugs. I recommend to have a look at the NIH cancer drug screening program at https://dtp.cancer.gov/discovery_development/nci-60/methodology.htm

You also find properties of the cell ines used (including doubliing time etc.)

I hope that will help you with further deccissions.

Best

Marc

Hi,

The IC50 versus GI50 indices are used as synonyms in the literature, while they are not translating exactly the same features from a biological point of view.

If you are using a colorimetric assay like the MTT popular one or the SRB one used by the NCI, the GI50/IC50 concentration refers to the concentration of the compound of interest that will reduce by 50% the growth of the treated cells as compared to the control ones after 48-72 h (depending on the labs) of culture in the presence of the compound.

As referenced in the instructions for authors of the Journal of Natural Products, a compound which is CYTOTOXIC and whose IC50/GI50 is > 10 µM should be considered as inactive, and this is also the position adopted by the NCI as referenced to you by Marc.

In contrast, if the compound is CYTOSTATIC, the GI50/IC50 "absolute concentration" will not be actually indicative of the anticancer "killing effects".

The attached article from Galluzzi and colleagues (from Guido Kroemer group) comprehensively describes the various cell death types.

We (Kornienko et al., J Med Chem 2013) have accordingly reviewed those compounds that induce the various cell death types described by Galluzzi et al. (2012).

The simple morphological analyses under phase-contrast microscopy while you are culturing your cells will easily indicate you if your compound is rather cytotoxic or rather cytostatic (see the attached articles).

From a more than gross point of view:

* if the morphological analyses clearly indicate cytotoxic effects after 72h of culturing at the GI50 concentration revealed by a colorimetric assay, then you can conclude that the sensitivity of your cell line(s) for your compound of interest ranges between xx and xx µM (depending on the number of cell lines analyzed).

* if cytotoxic, your compound can be considered as:

- highly active if its GI50 is < 1 µM

- active if its GI50 is ranging between 1 and 10 µM,

- inactive if its GI50 is > 10 µM

You can make exactly the same reasoning in terms of the sensitivity (highly sensitive - moderately sensitive - weakly sensitive) if you are taking into account the cut-off values indicated above, but IF and ONLY IF your compound of interest is cytotoxic;

* if the morphological analyses tend to bring you on a "cytostatic conclusion", the story becomes more complicated...

If needed, I am ready to help you on concrete examples generated from your own studies.

Best regards,

Robert

Hi, Marc and Robert,

Thank you for the detailed information on my question. it seems there are a lot to be learned. 

Dear

you can find such a this article:

Predict drug sensitivity of cancer cells with pathway activity inference

Abstract

Predicting cellular responses to drugs has been a major challenge for personalized drug therapy regimen. Recent pharmacogenomic studies measured the sensitivities of heterogeneous cell lines to numerous drugs, and provided valuable data resources to develop and validate computational approaches for the prediction of drug responses. Most of current approaches predict drug sensitivity by building prediction models with individual genes, which suffer from low reproducibility due to biologic variability and difficulty to interpret biological relevance of novel gene-drug associations. As an alternative, pathway activity scores derived from gene expression could predict drug response of cancer cells.

Method

In this study, pathway-based prediction models were built with four approaches inferring pathway activity in unsupervised manner, including competitive scoring approaches (DiffRank and GSVA) and self-contained scoring approaches (PLAGE and Z-score). These unsupervised pathway activity inference approaches were applied to predict drug responses of cancer cells using data from Cancer Cell Line Encyclopedia (CCLE).

Results

Our analysis on all the 24 drugs from CCLE demonstrated that pathway-based models achieved better predictions for 14 out of the 24 drugs, while taking fewer features as inputs. Further investigation on indicated that pathway-based models indeed captured pathways involving drug-related genes (targets, transporters and metabolic enzymes) for majority of drugs, whereas gene-models failed to identify these drug-related genes, in most cases. Among the four approaches, competitive scoring (DiffRank and GSVA) provided more accurate predictions and captured more pathways involving drug-related genes than self-contained scoring (PLAGE and Z-Score). Detailed interpretation of top pathways from the top method (DiffRank) highlights the merit of pathway-based approaches to predict drug response by identifying pathways relevant to drug mechanisms.

Conclusion

Taken together, pathway-based modeling with inferred pathway activity is a promising alternative to predict drug response, with the ability to easily interpret results and provide biological insights into the mechanisms of drug actions.

Regards