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Published on: May 20, 2016
Murine pulmonary adenoma bioassay of potentially effective agents against slow-growing solid tumors
Abstract:
An in vitro-in vivo system for screening potentially effective drugs against solid tumors is described. Drug toxicity to plateau-phase pulmonary adenoma cells is used as an in vitro screen for potential activity against solid tumors, since both plateau phase cultured cell populations and solid tumors are composed predominantly of nondividing cells. The effect of drugs with in vitro activity on the rate of appearance of urethan-induced adenomas on the lung surface of strain A mice in vivo is used to assess drug efficacy in the treatment of solid tumors, taking into consideration drug toxicity to and drug metabolism by the host. Arabinosylcytosine and hydroxyurea were ineffective against plateau phase cells in vitro, even at high concentrations (5 to 10 mg/ml), and did not affect pulmonary adenoma growth in vivo, even at toxic doses (arabinosylcytosine, 80 mg/kg; hydroxyurea, 800 mg/kg), as would be expected with these cell cycle-active drugs. Adriamycin, an effective agent against human solid tumors, was cytotoxic to plateau phase cultured cells (0% survivors at 1 mug/ml), and a dose of 2 mg/kg completely inhibited pulmonary adenoma growth in mice. Thus, this pulmonary adenoma bioassay would appear to effectively select for drugs which may be active against solid tumors in humans.
Insights
A novel in vitro-in vivo system screens solid tumor drugs using non-dividing cells. This pulmonary adenoma bioassay effectively identifies potential anti-cancer agents like Adriamycin for human solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Solid tumors and plateau-phase cell cultures share a predominance of non-dividing cells.
- Screening drugs against non-dividing cells may predict efficacy against solid tumors.
- Existing drug screening models do not adequately represent the cellular state of solid tumors.
Purpose of the Study:
- To describe a novel in vitro-in vivo system for screening potential anti-cancer drugs against solid tumors.
- To validate the use of plateau-phase pulmonary adenoma cells as an in vitro model for solid tumor screening.
- To assess drug efficacy in vivo using a pulmonary adenoma bioassay in mice.
Main Methods:
- Developed an in vitro screen using plateau-phase pulmonary adenoma cells to assess drug toxicity.
- Evaluated in vitro active drugs in vivo by monitoring urethane-induced pulmonary adenoma growth in strain A mice.
- Considered host toxicity and drug metabolism in the in vivo assessment.
Main Results:
- Arabinosylcytosine and hydroxyurea were ineffective both in vitro and in vivo, consistent with their cell cycle-specific activity.
- Adriamycin demonstrated cytotoxicity to plateau-phase cells in vitro and completely inhibited pulmonary adenoma growth in vivo at a dose of 2 mg/kg.
- The pulmonary adenoma bioassay successfully distinguished between ineffective and potentially effective anti-cancer drugs.
Conclusions:
- The described in vitro-in vivo system effectively screens for drugs potentially active against solid tumors.
- Plateau-phase pulmonary adenoma cells serve as a relevant model for predicting anti-cancer drug efficacy.
- This pulmonary adenoma bioassay is a valuable tool for identifying novel therapeutic agents for solid tumors.
