It is to understand 1) if the compound is "active", 2) if active at which concentration, and 3) what is the mechanism of action on cancer cell at the IC50 concentration.

For example cytotoxic pro-apoptotic drugs do not more meet unmet oncological need because cancers associated with dismal prognoses (such as metastatic cancers) are resistant to pro-apoptotic insults.

Thus, the in vitro data bring you a rather pretty good view about the effects of a given drug on cancer cells.

The problem is that a cancer is much more complex than the sole cancer component (because of the tumor microenvironment) and actual metastatic process cannot be studied in vitro.

Thus, in vitro studies can eliminate compounds that are not interesting and/or promising.

In vivo data are mandatory to study the effects of a drug in "real cancer biological conditions", including the metastatic process and the tumor microenvironment, and among others cancer heterogeneity, cancer stem cells, metastasis dormancy, etc..., etc....

The attached articles illustrate some of these facts.

Best regards

Robert

I agree with your answer, Dr. Robert. In the same sense, the cytotoxic studies can help to understand the proceeding mechanism, the real potentiality, the main molecular events involved, etc.

Thank you Imilla.

Kind regards

Robert

OK thanks. I got it. By the way with regard to the link below

https://www.researchgate.net/post/How_can_I_calculate_animal_dose_from_IC50

Dr Robert Kiss, with regard to in vivo tests, instead of random starting with 0.63 - 1.25 - 2.5 - 5.0 - 10.0 mg/Kg, will it be better to start with the IC50 value from MTT test as minimum dose, then 2nd one to make it 10 times of IC50 and from third onwards we will go 2 fold increase from 2nd dose which was 10 folds of IC50. The reason of making 10 folds to 2nd one is due to information saying that actual therapeutic dose in vivo is about 10 times of IC50. Thanks. 

How can I calculate animal dose from IC50? - ResearchGate. Available from: https://www.researchgate.net/post/How_can_I_calculate_animal_dose_from_IC50#57203f0e3d7f4b531b478a6d [accessed Apr 27, 2016].

Dr Robert kiss, I also would like to know after in vitro screening of compound with breast cancer cell lines, is that correct to go for next step such as  toxicity tests in vivo with 2 different animal species before clinical studies? 

AlsoTell me whether we are required to do two separate in vivo tests  to find out toxicity, and to find out therapeutic dose?

I am also want to clarify whether toxicity tests are done on both normal mice and diseased mice or just on normal mice. 

Dear Jamail,

I do not share the "strategy" that is proposed in the link you attached in your response.

You can calculate in vivo active dose only when you have the complete PK dynamics by i.p., per os and i.v. route ...

It is scientific nonsense to claim that "actual therapeutic dose in vivo is about 10 times of IC50", without having the full picture on PK dynamics + tissue distribution + tumor retention ... etc ... etc ...

Yes you are right: a compound must be "toxicologically" submitted to two different species before entering clinical trials. But you cannot do it by yourself. This must be done by a CRO that is FDA-approved. And you have to keep in mind that the budget for such toxicological analyses will costs several Keuro before receiving the authorization to enter clinical trials. And the toxicological part is one part of the dossier that is required by the regulatory authorities ...

Are you setting up a company or are you willing to publish an article?

Best regards

Robert

Dear Jamail,

I went back on the "website" you indicate in your message above.

It is already a "Q&A" you generated and it seems to me that the responses (including mine and the ones by Adam Shapiro) were crystal clear ...

Best regards

Robert

I am just doing research and would like to know what are the next subsequent things after in vitro cytotoxicity assays. So, it seems to be done in Vivo toxicity tests, in Vivo anti-cancer effects. So, in this case, do we have to test in vivo anticancer effect first or in vivo toxicity tests are done before the anticancer effect? 

In some published papers, I noticed that they mentioned anti-cancer effect 1st before acute toxicity and so on. Thanks

Dear Jamail,

First step: having in hands a compound that is original from the chemistry point of view.

Second step: challenging the compound in vitro in validated pharmacological tests.

Third step: deciphering partly the mechanism of action.

Option 1: publishing.

Option 2: adding proof of in vivo anticancer activity.

Then: publishing.

This is the goal of academic research.

Drug development is made within companies.

Best regards

Robert

Thanks Dr Robert. 

Hello Dr Robert, Need a bit of clarification with regard to the following para which was from the link mentioned. Below is the PARA of your reply from the link, 

"In contrast, if a death occur during the chronic treatment, you have to repead the toxicological analyses at MTD/2 if the first death occured at the end of the series of i.p. injections, at MTD/4 if the first death appeared during the chronic treatment, and at MTD/8 if death occured early."

Link: https://www.researchgate.net/post/How_can_I_calculate_animal_dose_from_IC50#57203f0e3d7f4b531b478a6d

Could you pls tell me what are "at MTD/2, at MDT/4 and at MTD/8"  mentioned in the above para with related to your input in that link? I did not get what you meant for that part. Thanks

MTD/2 is the Maximal Tolerated Dose divided by 2

MTD/4 .... divided by 4,

etc.

I am attaching here two of our articles illustrating you how we proceeded with this type of toxicological analyses and the determination of the drug concentration to be administered in vivo.

Best regards

Robert

 Oh.. I See. Thank You. I understand Dr Robert Kiss.