Secondary screening system for preclinical testing of human lung cancer therapies.
The National Cancer Institute has instituted a primary screening system for testing new agents against cultured cancer cell lines. The purpose of this study was to determine the feasibility of using a nude rat orthotopic (organ-specific) human lung cancer model system as an in vivo secondary screen for general evaluation of new anticancer agents and therapies active against lung cancer. To make this determination, we tested whether this system allows measurement of uptake and tumoricidal activity of anticancer therapies. Tumor-bearing lungs from 53 Rowett nude rats with orthotopically implanted human large-cell undifferentiated lung carcinoma (NCI-H460) were perfused ex vivo for 1 hour with or without each of two anticancer modalities. Lungs were perfused with blood-free perfusate alone (untreated control), perfusate with 100 micrograms/mL doxorubicin (treated positive control), or perfusate with lymphokine-activated killer cells plus human recombinant interleukin-2 (LAK/rIL-2). Weight gain during perfusion was the criterion used to quantitate lung injury. Treatment efficacy was measured by clonogenic assay after enzymatic disaggregation of the perfused tumors. Doxorubicin levels in the tumor and in the uninvolved lung were measured by high-performance liquid chromatography. Both treatment groups showed only slight increases in lung weight compared with that in the untreated control group, suggesting good lung tolerance of the procedure. Lung and tumor levels of doxorubicin were 320 +/- 21 ng/mg of tissue and 32 +/- 5 ng/mg of tissue (means +/- SE), respectively. Clonogenic assay demonstrated a fivefold to 10-fold reduction in the surviving fraction of tumor cells with doxorubicin but no change with LAK/rIL-2.(ABSTRACT TRUNCATED AT 250 WORDS)
Mulvin
D W
DW
Department of Surgery, University of Colorado School of Medicine, Denver.
Howard
R B
RB
Mitchell
D H
DH
Noker
P E
PE
Kruse
C A
CA
Chu
H D
HD
Bunn
P A
PA
Johnston
M R
MR
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D015979:Killer Cells, Lymphokine-Activated / Q000502:physiology; D008175:Lung Neoplasms / Q000378:metabolism / Q000628:therapy*; D009368:Neoplasm Transplantation; D010477:Perfusion; D051381:Rats; D011923:Rats, Nude; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D004317:Doxorubicin