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Preclinical Development: Overview

Preclinical Development: Overview

Preclinical development consists of a series of tests that ensure the safety and efficacy of a new therapeutic compound before it is tested in humans. There are four main phases to this process. First, safety pharmacology tests are conducted to ensure the drug does not produce any acutely harmful effects. These tests examine parameters such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes, and ataxia. Next, preliminary toxicological testing is performed to determine the...

Toxicity Testing in Animals

Toxicity Testing in Animals

Toxicity tests in animals are grounded on two main assumptions: first, the effects observed in laboratory animals can be extrapolated to humans, especially when adjusted for body surface area; second, high-dose exposure in animals is essential to identify potential human hazards from lower doses. This is based on the quantal dose-response concept, which faces the challenge of extrapolating results from relatively few test animals to much larger human populations. For example, a 0.01% incidence...

Clinical Trials: Overview

Clinical Trials: Overview

Clinical development focuses on how the drug will interact with the human body and encompasses four key phases of clinical trials, each serving a specific purpose in assessing the safety and effectiveness of new drugs. These phases overlap and build upon one another. Phase I involves a small group of healthy volunteers (typically 20-80 individuals) or, in cases where significant toxicity is expected, patients with the targeted disease, such as cancer or AIDS. The volunteers are tested for...

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Initial testing of topotecan by the pediatric preclinical testing program.

Hernan Carol¹, Peter J Houghton, Christopher L Morton

¹Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.

Pediatric Blood & Cancer

|December 18, 2009

Summary

Topotecan, a DNA topoisomerase I poison, showed significant antitumor activity in preclinical models of pediatric solid tumors and acute lymphoblastic leukemia (ALL). These findings validate the Pediatric Preclinical Testing Program (PPTP) tumor models for drug development.

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Area of Science:

Oncology
Pharmacology
Cancer Research

Background:

Topotecan is a DNA topoisomerase I inhibitor with prior success in pediatric cancer clinical trials.
The Pediatric Preclinical Testing Program (PPTP) was used to validate preclinical models for pediatric cancers.

Purpose of the Study:

To evaluate the antitumor activity of topotecan against pediatric solid tumor and acute lymphoblastic leukemia (ALL) xenografts.
To assess the validity of the PPTP tumor panels for preclinical drug testing.

Main Methods:

In vivo assessment of antitumor activity using objective response, T/C tumor volume, and event-free survival (EFS) measures.
Testing topotecan against panels of pediatric solid tumor and ALL xenografts.

Main Results:

Topotecan demonstrated significant in vitro growth inhibition (0.71-489 nM IC50).
Topotecan significantly increased EFS in 87% of solid tumors and 100% of ALL xenografts.
Objective responses were observed in eight solid tumors, including neuroblastomas, and several complete and partial responses were seen in ALL models.

Conclusions:

Topotecan exhibits broad in vitro and in vivo anticancer activity against pediatric solid tumors and ALL.
The PPTP tumor panels are validated as effective models for preclinical evaluation of novel anticancer agents.