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Responsiveness of human lung cancer/nude mouse to antitumor agents in a model using clinically equivalent doses
T Tashiro1, M Inaba, T Kobayashi
1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Abstract:
The responses of 14 lines of human lung cancer xenografts in BALB/c-nu/nu mice to eight known antitumor agents were investigated. These xenografts consisted of four small-cell carcinomas (SCLC) and ten non-small-cell carcinomas (four large cell, three squamous cell, and three adenocarcinomas; NSCLC). The doses used in the experiments were the maximum tolerated dose (MTD) in nude mice and the "rational dose" (RD), the latter considered to be pharmacokinetically equivalent to the clinical dose. When given at MTDs, all drugs except 5-fluorouracil (5-FU) and methotrexate (MTX) were extremely effective against NSCLC as well as SCLC. The response rates of drug-sensitive SCLC to mitomycin C (MMC), ACNU, and vinblastine (VLB) were 100%, and those to Adriamycin (ADR) and vincristine (VCR) were 75%. In addition, the response rates of even drug-resistant NSCLC to MMC and VLB were 70% and 90%, respectively. In contrast, the response rates of NSCLC to RDs of the drugs were reduced to less than 40% and corresponded well to the respective clinical rates. In SCLC, a good correlation of experimental and clinical response rates was observed with four drugs [cyclophosphamide (CPM), ACNU, VLB, and 5-FU]. As a result, we emphasize that a more reasonable prediction of the clinical effectiveness of antitumor agents can be made by a protocol using clinically equivalent doses.
Insights
Predicting antitumor agent effectiveness in lung cancer xenografts requires clinically equivalent doses. Using rational doses (RDs) in mice better reflects human clinical response rates for both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC).
Area of Science:
- Oncology
- Pharmacology
- Preclinical Cancer Research
Background:
- Investigating the efficacy of antitumor agents in human lung cancer xenografts is crucial for drug development.
- Understanding the differences in xenograft response to various drug doses is key to predicting clinical outcomes.
Purpose of the Study:
- To evaluate the response of human small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) xenografts to known antitumor agents.
- To compare the effectiveness of maximum tolerated doses (MTDs) versus rational doses (RDs) in predicting clinical efficacy.
Main Methods:
- 14 human lung cancer xenograft lines (4 SCLC, 10 NSCLC) were treated with eight antitumor agents.
- Experiments utilized both maximum tolerated doses (MTDs) and rational doses (RDs), with RDs being pharmacokinetically equivalent to clinical doses.
Main Results:
- At MTDs, most drugs showed high efficacy against both SCLC and NSCLC.
- Response rates for NSCLC treated with RDs were <40%, correlating well with clinical rates.
- A good correlation between experimental and clinical response rates was observed in SCLC using specific drugs at RDs.
Conclusions:
- Predicting clinical effectiveness of antitumor agents is more reliable using protocols with clinically equivalent doses (RDs).
- The study highlights the importance of dose selection in preclinical models for accurate translation to human cancer therapy.