Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy.
OBJECTIVE
Potential causes of drug resistance in solid tumors include genetically determined factors expressed in individual cells and those related to the solid tumor environment. Important among the latter is the requirement for drugs to penetrate into tumor tissue and to achieve a lethal concentration in all of the tumor cells. The present study was designed to characterize further the multicellular layer (MCL) method for studying drug penetration through tumor tissue and to provide information about tissue penetration for drugs used commonly in the treatment of human cancer.


METHODS
EMT-6 mouse mammary and MGH-U1 human bladder cancer cells were grown on collagen-coated semiporous Teflon membranes to form MCLs approximately 200 microm thick. The properties of MCLs were compared with those of tumors grown in mice from the same cells. The penetration of drugs through the MCL was evaluated by using radiolabeled drugs or analytical methods.


RESULTS
The MCL developed an extracellular matrix containing both laminin and collagen, although there were some differences in expression of extracellular matrix proteins. Electron microscopy showed rare desmosomes in both MCL and tumors. The penetration of cisplatin, etoposide, gemcitabine, paclitaxel, and vinblastine through tissue in the MCL was slow compared with penetration through the Teflon support membrane alone.


CONCLUSIONS
Our results suggest limited ability of anticancer drugs to reach tumor cells that are distant from blood vessels. The limited penetration of anticancer drugs through tumor tissue may be an important cause of clinical resistance of solid tumors to chemotherapy.
Tannock
Ian F
IF
Department of Medical Oncology and Hematology and the Division of Experimental Therapeutics, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, M5G 2M9 Canada. ian.tannock@uhn.on.ca
Lee
Carol M
CM
Tunggal
Jonathon K
JK
Cowan
David S M
DS
Egorin
Merrill J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D002945:Cisplatin / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004058:Diffusion; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000493:pharmacokinetics; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D008567:Membranes, Artificial; D051379:Mice; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000493:pharmacokinetics; D011138:Polytetrafluoroethylene; D014407:Tumor Cells, Cultured / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*; D014747:Vinblastine / Q000493:pharmacokinetics; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D008567:Membranes, Artificial; D003841:Deoxycytidine; D014747:Vinblastine; D005047:Etoposide; D011138:Polytetrafluoroethylene; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine