Distribution and activity of antineoplastic drugs in a tumor model.
Antineoplastic drugs can be effective in solid tumors only if they can penetrate several cell layers and retain their activity in the tumor microenvironment. The capacity of several common chemotherapeutic agents to meet these requirements was evaluated in an in vitro tumor model, V79 Chinese hamster cells grown as spheroids. The delivery and toxicity of radioactively labeled 5-fluorouracil, lomustine, tetraplatin, and chlorambucil were determined by use of cell-sorting techniques to select cells as a function of their position (depth) within these spheroids, and the delivery and toxicity of doxorubicin (DOX) were evaluated on the basis of fluorescence intensity. Simultaneous measurement of drug level and toxicity in cells at the time of recovery from different depths within the spheroids led to the conclusion that drug delivery was a problem only for DOX. In contrast, several of the other agents showed a dissociation between cellular drug levels and activity, implicating a major role of the cellular microenvironment in modulating drug toxicity.
Durand
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Medical Biophysics Unit, B.C. Cancer Research Centre, Vancouver, Canada.
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004317:Doxorubicin / Q000494:pharmacology; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology; D008130:Lomustine / Q000493:pharmacokinetics / Q000494:pharmacology; D008954:Models, Biological; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D008130:Lomustine; D004317:Doxorubicin; C049777:ormaplatin; D005472:Fluorouracil