Anticancer drugs from land and sea

(Second of two parts)

If drugs could be specifically and selectively targeted to cancer cells, i.e., normal cells are spared, then cancer patients would not have to suffer the toxic side effects of chemotherapy. One way is to make use of antibodies that could bind specifically to TAAs (tumor-associated antigens) or TSMs (tumor surface markers). In AML, the drug that is used as a last resort (when all else fails) is an antibody targeted drug or immunotoxin known as Myelotarg.

Myelotarg consists of a humanized antibody called anti-CD33 that is chemically linked to calicheamicin g1, a highly toxic compound that has an unusual enediyne chemical structure (that binds and then breaks DNA) which was first isolated from a terrestrial actinomycete (a bacterium) identified as Micromonospora echinospora. CD33 is a unique marker found on the surface of AML blast cells. Anti-CD33 (antibody to CD33) is a mouse monoclonal antibody that was generated against CD33 by injecting human CD33 in mice. Anti-CD33 was “humanized” so that it could be used for protracted therapy (humanized meaning the mouse antibody protein was modified to look like a human protein so that during therapy, the human immune system will not reject it as a foreign substance). Myelotarg or the anti-CD33-calicheamicin immunotoxin conjugate behaves like a magic bullet or guided missile that hones in on AML cancer cells and spares normal cells.

In my laboratory at the UP Marine Science Institute, we have been isolating compounds from marine sponges and microorganisms with potential anticancer activity. Adociaquinone B, isolated from a Xestospongia sp. sponge, behaves as a TOPO 2 poison just like doxorubicin. Heptyl prodigiosin, from a marine strain of the bacterium Pseudovibrio denitrificans, induces apoptosis in cancer cells. Administered together, the two compounds act synergistically to kill breast cancer cells. We continue to explore marine organisms as a rich source of anticancer compounds. And we too have explored targeted therapy by linking our marine molecules to antibodies targeted to cancer cells.

Most of the anticancer drugs I mentioned above came from natural sources or were modeled from natural compounds. Doxorubicin, also known as adriamycin, was first isolated from a bacterium in the Adriatic Sea, and there are now several other marine compounds in the market or in clinical trials, e.g., ecteinascidin 743 (Yondelis), discodermolide. Taxol, vincristine and etoposide came from plants, and irinotecan was modeled after camptothecin, also from a plant. And so our colleagues at the UP Institutes of Chemistry and Biology are also exploring plant natural products as a source of anticancer and cancer preventive compounds.

Clearly, there is reason for us to explore Philippine biodiversity, which is one of the richest in the world, as a source of new drugs. It is not surprising that Nature has provided most of the anticancer drugs useful to humans. These bioactive compounds are actually secondary metabolites produced by the source organisms to fight competitors, ward off predators and parasites, kill prey, compete for space, regulate or inhibit growth, etc.; in short, for defense and survival (and to function as they would against cancer!). And what’s good is that their chemical properties and biological activity have already been field-tested through millions of years of evolution (as opposed to synthetic drugs that are selected based on limited chemical frameworks and pharmacological testing).

However, it is known that anticancer drugs don’t always work. Ara-C didn’t really work for my friend. It worked for a while and then it failed. Her AML recurred a few times. That’s because cancer is the most complex of all diseases and cancer cells have the genetic capability to resist the drugs. One cancer cell that survives chemotherapy over the millions of cells that didn’t can trigger a recurrence of the cancer. But…my friend is well today, and I’ll tell you why in another article. I believe there is hope for those with cancer.

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Gisela P. Padilla-Concepcion, Ph.D., is a professor of the Marine Science Institute and chair of the Dean’s Office on Special Initiatives for the Advancement of Science, College of Science, UP Diliman. She teaches graduate courses in marine natural products and marine biotechnology and leads the PharmaSeas and PMS (Philippine Mollusk Symbiont)-ICBG research programs at UP MSI. She is a member of the National Academy of Science and Technology. E-mail her at [email protected]