On 2014 Aug 16, Miguel Lopez-Lazaro commented:

Improving Selectivity versus Improving Cytotoxicity

This article reports that a 2'-modified-4'-selenoarabinofuranosyl-pyrimidine improves the cytotoxic potency of the standard anticancer drug cytarabine (ara-C) in several human cancer cell lines. Like most researchers involved in anticancer drug discovery, the authors evaluate the in vitro anticancer potential of their compounds addressing the question: Can my compounds improve the cytotoxicity of the standard anticancer drugs?

We typically assess the in vitro therapeutic potential of our compounds following a cytotoxic potency-based approach: the lower the concentration required to kill cancer cells, the higher the potential for cancer therapy (I have followed this approach many times in the past; e.g., http://www.ncbi.nlm.nih.gov/pubmed/23174318). Despite its widespread use, this approach is illogical and unreliable.

Cancer patients do not need drugs that kill their cancer cells at low concentrations. They need drugs that kill their cancer cells at concentrations that do not significantly affect their normal cells; otherwise, the maximum doses tolerated by the patients will be insufficient to reach the drug concentrations required to eliminate the cancer cells of their bodies. If a drug kills cancer cells without affecting nonmalignant cells, it does not really matter at what concentrations it kills the cancer cells.

It is also important to note that the ability of a compound to kill cancer cells at low concentrations does not reliably predict its ability to kill cancer cells selectively. Therefore, when we show that our compounds kill cancer cells at low concentrations, we are not revealing whether or not they have potential for cancer therapy.

To properly reveal the in vitro therapeutic potential of our compounds, we only need cancer cells, nonmalignant cells, standard anticancer drugs, a simple cytotoxicity test, and an answer to the question: Can my compounds improve the ability of the standard drugs to kill cancer cells without significantly affecting nonmalignant cells from appropriate tissues? (1).

A basic protocol for addressing this question can be found in reference (1). I can also e-mail a copy of the screening protocol included in this reference to anyone who requests it at mlopezlazaro@us.es

The authors should consider using this selectivity-based approach to assess if their compounds improve the selectivity of cytarabine; this would reveal their cancer therapeutic potential. Meanwhile, readers should interpret the findings of this article with caution.

(1) Lopez-Lazaro, M. Experimental Cancer Pharmacology for Researchers: At What Concentration Should my Drug Kill Cancer Cells so that it has Potential for Cancer Therapy? 2014, ASIN: B00MMO25NM http://www.amazon.com/dp/B00MMO25NM/

On 2014 Aug 16, Miguel Lopez-Lazaro commented:

Improving Selectivity versus Improving Cytotoxicity

This article reports that a 2'-modified-4'-selenoarabinofuranosyl-pyrimidine improves the cytotoxic potency of the standard anticancer drug cytarabine (ara-C) in several human cancer cell lines. Like most researchers involved in anticancer drug discovery, the authors evaluate the in vitro anticancer potential of their compounds addressing the question: Can my compounds improve the cytotoxicity of the standard anticancer drugs?

We typically assess the in vitro therapeutic potential of our compounds following a cytotoxic potency-based approach: the lower the concentration required to kill cancer cells, the higher the potential for cancer therapy (I have followed this approach many times in the past; e.g., http://www.ncbi.nlm.nih.gov/pubmed/23174318). Despite its widespread use, this approach is illogical and unreliable.

Cancer patients do not need drugs that kill their cancer cells at low concentrations. They need drugs that kill their cancer cells at concentrations that do not significantly affect their normal cells; otherwise, the maximum doses tolerated by the patients will be insufficient to reach the drug concentrations required to eliminate the cancer cells of their bodies. If a drug kills cancer cells without affecting nonmalignant cells, it does not really matter at what concentrations it kills the cancer cells.

It is also important to note that the ability of a compound to kill cancer cells at low concentrations does not reliably predict its ability to kill cancer cells selectively. Therefore, when we show that our compounds kill cancer cells at low concentrations, we are not revealing whether or not they have potential for cancer therapy.

To properly reveal the in vitro therapeutic potential of our compounds, we only need cancer cells, nonmalignant cells, standard anticancer drugs, a simple cytotoxicity test, and an answer to the question: Can my compounds improve the ability of the standard drugs to kill cancer cells without significantly affecting nonmalignant cells from appropriate tissues? (1).

A basic protocol for addressing this question can be found in reference (1). I can also e-mail a copy of the screening protocol included in this reference to anyone who requests it at mlopezlazaro@us.es

The authors should consider using this selectivity-based approach to assess if their compounds improve the selectivity of cytarabine; this would reveal their cancer therapeutic potential. Meanwhile, readers should interpret the findings of this article with caution.

(1) Lopez-Lazaro, M. Experimental Cancer Pharmacology for Researchers: At What Concentration Should my Drug Kill Cancer Cells so that it has Potential for Cancer Therapy? 2014, ASIN: B00MMO25NM http://www.amazon.com/dp/B00MMO25NM/