Back to Doses... Again!?!It is easy to see that there are a lot of new people on here... we covered this topic in August. I did email Pharmagap to clear up this question... It is a high dose for NCI (their second highest dose) but a low dose for GAP. It has more to do with the G150 than anything else. Below is the letter from Gap and under that is some info on G150. If you have more questions let me know and I can post more on the doses and on the NCI testing.
Karen,
10 uM may be a “high end” dose at NCI but for a peptide drug it is a low concentration, as per our news release. In any event, its not the concentration per se that matters. It’s the GI50 (50% growth inhibition) that is the important metric and that will fall out of the 5-dose study now underway.
Thanks for your interest.
Simon Goulet
EVP & Chief Operating Officer
100 Sussex Drive Ottawa Ontario K1A 0R6 Canada
Tel: (613)991-5370 Fax: (613)998-3399
simon.goulet@pharmagap.com
Concentration Parameters GI50, TGI, and LC50
The NCI renamed the IC50 value, the concentration that causes 50% growth inhibition, the GI50 value to emphasize the correction for the cell count at time zero; thus, GI50 is the concentration of test drug where 100 × (T - T0)/(C - T0) = 50 (3, 9). The optical density of the test well after a 48-h period of exposure to test drug is T, the optical density at time zero is T0, and the control optical density is C. The ``50'' is called the GI50PRCNT, a T/C-like parameter that can have values from +100 to -100. The GI50 measures the growth inhibitory power of the test agent. The TGI is the concentration of test drug where 100 × (T - T0)/(C - T0) = 0. Thus, the TGI signifies a cytostatic effect. The LC50, which signifies a cytotoxic effect, is the concentration of drug where 100 × (T - T0)/T0 = -50. The control optical density is not used in the calculation of LC50.
These concentration parameters are interpolated values. One uses the concentrations giving GI50PRCNT values above and below the reference values (e.g., 50 for GI50) to make interpolations on the concentration axis. Currently, about 45% of the GI50 records in the database are ``approximated''. In 42% of the records, the GI50PRCNT for a given cell line does not go to 50 or below. For mean graph (see the discussion later) and COMPARE purposes, the value assumed for the GI50 in such a case is the highest concentration tested (HICONC). Similar approximations are made when the GI50 cannot be calculated because the GI50PRCNT does not go as high as 50 or above (3% of total). In this case, the lowest concentration tested is used for the GI50. Corresponding approximations are made for the TGI and for the LC50.
We use these ``approximated'' GI50 (TGI and LC50) values in the mean graph and in COMPARE because they represent valued information even though the information is less exact than the measured values would be if the measured values were available. In an extreme case where a compound is essentially inert and the GI50s are all represented by the HICONC approximation, the mean graph becomes a flat vertical line (the mean line) and COMPARE has no pattern to correlate. The opposite extreme case is where a compound is so potent that the lowest concentration tested is used to approximate all of the GI50s. In this case, the mean graph is also a flat vertical line and COMPARE has nothing to correlate. The difference in the two extreme cases is in the retests that are done. The inert compound would not be retested. The potent compound would be retested at a more appropriate concentration range.
Between the two extremes are examples with few or many approximated GI50s. These can give good results in COMPARE, but the presence of the approximated GI50 requires an additional strategy in the database preparation. The strategy is to treat the data for a given compound in groups defined by the range of concentrations used in the experiment. These ranges are conveniently labeled according to the HICONC. Thus, if multiple tests of a compound are present in the database, only those experiments with the same HICONC are averaged.
This strategy results in compounds having more than one entry in the database. There are differences in the ``approximated'' GI50 content of the averaged data, and the averages are calculated from different experiments. Therefore, one should expect that the COMPARE-generated correlation coefficients may be different for the same compound tested at different HICONCs. Moreover, at run time the COMPARE user has the option to choose any one of the HICONC sets for the probe pattern averaging, or the user may choose to average all seed data regardless of the HICONC. The consequences of these options and strategies will be apparent later in the examples provided under Applications of COMPARE. For instance, the probe may find itself several times in the COMPARE list at less than 1.00 correlation coefficient.