n where the cells grew. Breast tumors grown in the brain, for example, had blood vessels with much smaller pores than did tumors grown under the skin. Pore size was also greatly reduced in the shrunken hormone-dependent tumors. In fact, withdrawal of testosterone resulted in a reduction of pore size from 200 nanometers (nm) to less than 7 nm within 48 hours in a testosterone-dependent tumor.

"That tells you that you just can't make a drug and expect it to work on all tumors," says Jain. Sue Hobbs and Wayne Monsky, an MD-PhD student and postdoctoral fellow, respectively, in Jain's lab, are lead authors on the paper.

The study casts new light on some old cancer puzzles. For example, some anticancer agents that work well in the petri dish fail to kill cancer cells in the body. The new findings suggest that such candidate drugs may never get a chance to prove their cancer-killing powers because they have been engineered too large for the microscopic doors they have to pass through.

Equally perplexing, some chemotherapies lose their efficacy after only a few rounds. Many have chalked up these failures to the development of resistance -- when successive rounds of chemotherapeutic agents allow impervious mutants to gain a foothold. "You can't talk about multidrug resistance if you can't get the drugs into the tumor," says Jain. He believes there is another explanation for such disappointing results: chemotherapeutic agents may, by shrinking tumors, be shrinking blood vessel pores -- in effect, closing the door behind them.

The implications are that drug makers must not only design agents that get through a variety of microscopic doors, they must also think about aiming their drugs at a moving target -- blood vessel pores that change in size over the course of treatment. Yet drug companies have been taking a one-size-fits-all approach, Jain says. In the area of gene therapy, the trend has been to design bigger and more impressive
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Contact: Bill Schaller
schaller@hms.harvard.edu
617-432-0441
Harvard Medical School
14-Apr-1998

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