Flooding the body with chemotherapy drugs in hopes of knocking out an isolated tumor has been one modus operandi of treating cancer for many decades. But the side effects of this kind of blanket coverage can sometimes be as debilitating as the disease itself. For that reason, researchers are looking at better ways to target therapies to treat cancer and reduce unwanted side effects.
Difficult to Target
According to Esmail Tabibi, Ph.D., of the Pharmaceutical Resources Branch at the National Cancer Institute, biological heterogeneity of tumors, unidentified targets, and other factors make it difficult in most adult cases to deliver the right drug to the right tumor at the right site of action with the right duration and at the right concentration to result in a successful therapy.
Edward Sausville, M.D., Ph.D., associate director of NCIs Developmental Therapeutics Program, noted that "tumors are a succession of compartments comprised of vessels, interstitial components, and internal cellular compartments, each of which can affect delivery strategies and alter location of the drug within the tumor." Sausville added that the treatment dilemmas that scientists face are the very narrow therapeutic index, or range between toxic dose and effective dose, and the lack of a large difference in the toxic effect of treatments between tumor and normal cells.
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Unique Target
Building on Aus thoughts, Hiroshi Maeda, M.D., Kumamoto University School of Medicine, Kumamoto, Japan, noted that "tumor vascular biology has a particular dynamic and can be a unique target for macromolecules."
Based on an understanding of tumor vascular dynamics, Jindrich Kopecek, Ph.D., of the University of Utah, Salt Lake City, developed a drug called HPMA-conjugated doxorubicin to try to take advantage of an enhanced permeability and retention phenomenon that targets anticancer drugs to solid tumors. Ruth Duncan, Ph.D., of the University of London School of Pharmacy, examined Kopeceks drug in hepatocellular carcinoma. Duncan said that the findings of efficacy and low toxicity support the fundamental rationale for design of targeted delivery systems. Another aspect of vascular dynamics that can affect the efficacy of targeted therapies was discussed by Liang Xu, M.D., Ph.D., Lombardi Cancer Center, Washington, D.C. Xu expressed concern about how time-dependent diffusion decreases effectiveness of drugs as they travel through capillaries in tissue.
But understanding vascular dynamics is only one aspect of creating better targeted therapies. A number of researchers are looking at recent successful targeted approaches as starting blocks for their future experiments.
Best Known Targeted Therapy
The drug Herceptin, which targets tumor cells overexpressing the protein HER2/neu, is probably the best known targeted therapy in the marketplace today. John Park, M.D., of the University of California at San Francisco, developed a novel, perhaps more specific and effective delivery system for the anti-HER2 monoclonal antibody. Park said his laboratory has come up with long circulating liposomes linked to anti-HER2 MAb fragments containing the drug doxorubicin that deliver it to the target tumor overexpressing HER2. Park notes that "some of the reasons that liposomes make good delivery systems are because of their stability in blood and plasma and that they can remain circulating for long periods of time."
Hayat A. Onyuksel, Ph.D., University of Illinois at Chicago, said that HER2 is not the only known protein that is overexpressed in breast cancer. In addition to HER2, Onyuksel said that vasoactive intestinal peptide receptors (VIP-R) are also overexpressed. Her laboratory, in a parallel to Parks work, has developed stabilized liposomes with VIP as a targeting site to deliver drugs to breast cancers overexpressing VIP-R.
Some of the more unusual types of treatments being developed as targeted therapies are derived from toxins such as salmonella, anthrax, and shiga-like organisms, which on their own can be dangerous and sometimes deadly. Ira Pastan, M.D., chief of the Laboratory of Molecular Biology at NCI, has been developing recombinant immunotoxins, which consist of a fragment of an antibody fused to a toxin. Pastan chose toxins because "they are very active, can kill cells, but are not toxic to bone marrow nor are they mutagenic."
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Instead of toxins, Christopher G. Wood, M.D., from the University of Texas M.D. Anderson Cancer Center, Houston, used adenoviruses as vectors or carriers to deliver chemotherapeutic agents to tumors. "The drug we developed acted only on the targeted tumor and not on other cells, and we saw increased apoptosis and tumor regression," said Wood. He also noted an increased response when repeated doses were administered.
Sausville said that "we are at a new stage in drug development that will need to turn away from building variations of standard agents."
He challenged the community by saying, "I make a point not to focus on drugs such as doxorubicin, cisplatin, and paclitaxel which, however, were certainly necessary to illustrate proof of principle. There are a lot of molecules out there which are not capable of being used in standard therapy because of their particular pharmacological features but may be uniquely qualified to be addressed by targeted strategies."
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