Floxuridine

Biochemistry

The seeds of better chemotherapy?

In recent years, oncologists have explored the prospects of injecting liposomes -- microscopic drug carriers constructed from fat-like chemicals -- to treat cancers. A pair of new studies strongly suggests that these drug-delivery vehicles may boost the safety or potency of anticancer drugs.

Doxorubicin "is the single most useful drug in breast cancer," says oncologist Joseph Treat at the Medical College of Pennsylvania in Philadelphia. However, the compound is also highly toxic to noncancerous tissue -- especially the heart.

Two years ago, Pieter Cullis at the University of British Columbia in Vancouver described animal data showing that liposome packaging dramatically reduced doxorubicin's normal cardiac toxicity (SN: 6/4/88, p.360). Treat, collaborating with cancer researchers from Georgetown University in Washington, D.C., and heart pathologists at the National Heart, Lung, and Blood Institute in Bethesda, Md., now reports similar doxorubicin protection in an uncontrolled trial involving 20 patients with advanced breast cancer -- each receiving an average of five high-dose intravenous infusions of drug-laced liposomes. These patients, Cullis says, provide "the first indication in humans that [liposome encapsulation] reduces cardiotoxicity."

Formerly, Treat observers, nearly every patient receiving cumulative doxorubicin doses of at least 180 milligrams per meter squared of body surface exhibited significant heart damage. At higher doses, some even developed congestive heart failure. But in the Nov. 7, 1990 JOURNAL OF THE NATIONAL CANCER INSTITUTE, his team reports that biopsies of patients receiving doses as high as 600 to 880 [mg/m.sup.2] showed little or no heart damage. This "almost complete lack of toxicity is remarkable" and "very, very significant," Treat told SCIENCE NEWS.

Moreover, the improved safety does not appear to come at the expense of doxorubicin's efficacy. The researchers report that nine of the treated individuals improved; five experienced a complete remission of their major metastatic tumor. Treat says he wants to follow up on these findings by participating in multi-institutional trials that compare the outcomes of patients randomly assignd to treatment with either regular doxo-rubicin or the liposome-encased drug.

Dutch researchers are now attempting to advance the liposome concept one step farther: They're incorporating anticancer drugs into low-density lipoproteins (LDLs).

With their spherical shape and high lipid content, these natura cholesterol-shuttling agents in the blood resemble liposomes. But LDLs offer two potentially dramatic advantages over conventional liposomes, according to P. Chris de Smidt and Theo J.C. van Berkel of the University of Leiden in The Netherlands. First, because cancerous tissues exhibit an unusually high "demand" for cholesterol, their cells develop high numbers of LDL receptors. As a result, injections of drug-laden LDLs should home in on malignancies more than on healthy tissues, the researchers say. Second, because the body tends to recognize LDLs as natural, de Smidt and van Berkel say drug-containing LDLs might be thought of as "stealth liposomes" -- lab-engineered cancer munitions that can evade the body's own defense against foreign substances.

Indeed, the Leiden pair reports in the Dec. 1, 1990 CANCER RESEARCH that two LDL-bound injected drugs -- methotrexate and floxuridine -- successfully dodged the body's natural clearance mechanisms to circulate at least six times longer in the blood of rats than did unbound drugs. Because the LDLs survived longer than the drugs they had been carrying, de Smidt and van Berkel say the drugs may not have been chemically bound to the LDLs firmly enough. But the findings are promising enough, they say, to warrant human investigation of these potential drug carriers.

COPYRIGHT 1991 Science Service, Inc.
COPYRIGHT 2004 Gale Group