Two preclinical tests to evaluate anticancer activity and to help validate drug candidates for clinical trials.

Miguel López-Lázaro

doi:10.18632/oncoscience.132

Abstract

Current approaches to assessing preclinical anticancer activity do not reliably predict drug efficacy in cancer patients. Most of the compounds that show remarkable anticancer effects in preclinical models actually fail when tested in clinical trials. We blame these failures on the complexity of the disease and on the limitations of the preclinical tools we require for our research. This manuscript argues that this lack of clinical response may also be caused by poor in vitro and in vivo preclinical designs, in which cancer patients' needs are not fully considered. Then, it proposes two patient-oriented tests to assess in vitro and in vivo anticancer activity and to help validate drug candidates for clinical evaluation.

Highlights

Many cancer patients are diagnosed with or develop distant metastasis
Since curcumin typically kills cancer cells in the 5-50 μM range [28], we evaluated its cytotoxic activity in lung cancer cells and lung nonmalignant cells at this concentration range and observed an identical cytototoxic profile in both cell lines [29]
It is broadly accepted that the limitations of preclinical tools, such as inadequate cancer cell lines and mouse models, make it difficult for even the best scientists working in optimal conditions to make a discovery that will have an impact in the clinic [9]

Summary

INTRODUCTION

Many cancer patients are diagnosed with or develop distant metastasis. Despite the recent approval of numerous anticancer drugs [1], most of these patients do not overcome the disease. Instead of looking for compounds that improve the selectivity (in vitro) and the survival rate (in vivo) of the existing pharmacological treatments, researchers typically look for compounds that target malignant cells at low concentrations and induce antitumor activity in animal models. The marked antitumor activity of these compounds in xenograft models is unlikely to be reproduced in clinical trials These tests are designed to detect whether or not an experimental treatment is better than the standard treatment used in cancer patients. They can be used as standalone tests to assess preclinical anticancer activity They are based on setting suitable experimental conditions to answer two questions: Can the drug candidate improve the ability of the existing drugs to selectively kill cancer cells versus a variety of nonmalignant cells? Because most patients requiring pharmacotherapy have metastatic disease, selecting animal models of metastasis should be a priority in most situations

Strengths and limitations of the tests

Findings

CONCLUDING REMARKS