Anticancer drugs from land and sea

(First of two parts)

Ten years ago, a close friend of mine who lives abroad was diagnosed with AML (acute myeloid leukemia). She was at the prime of her life. Cancer devastated her and her family, but she was by nature a fighter. With great courage and resolve, she underwent difficult, painful chemotherapy prescribed for AML. At critical times in her treatment, her sister and I travelled to be with her. She and her immediate family (husband and two young children) had no one else to turn to for advice. There was no medical doctor in their family.

Because I was involved in research on anticancer drugs from the sea, they believed I could be counted on for some guidance and advice. Today, my friend is alive, active, and strong. She has beaten the odds against AML for which the survival rate beyond 5 years is low. I recall telling her often to keep her fighting spirit strong, since every added year of survival could bring her a new, more effective drug, another new treatment, a perfect match for a transplant.

AML is a cancer of the myeloid line of blood cells. In AML, abnormal white blood cells grow rapidly, accumulate in the bone marrow and interfere with the production of normal blood cells, causing a drop in red blood cells, platelets, and normal white blood cells. The standard chemotherapy for AML is a drug known as Ara-C or cytarabine.

Ara-C is a synthetic drug that was modeled after Ara-T (spongothymidine) and Ara-U (spongouridine), two arabinonucleosides that were first isolated from the Caribbean sponge Tethya crypta in the 1950s. The discovery of these compounds gave birth to the field of anticancer marine natural products research which has flourished and received major funding from the US National Cancer Institute for many years. (Another synthetic drug, Ara-A or vidarabine, also modeled after the sponge compounds, is a potent antiviral drug used to treat herpes and other viral diseases.) Ara-C is an example of an anticancer drug that acts as an antimetabolite, i.e., the arabinose sugar competes with the ribose sugar which is part of a nucleotide, the natural building block or metabolite for DNA synthesis. And so Ara-C inhibits DNA synthesis and the cancer cells, as well as fast growing normal cells, die.

Other anticancer drugs (used for other types of cancer) act on DNA in other ways. They can be intercalating agents (insert between the base pairs of DNA, e.g., anthracyclines), alkylating agents (form a covalent alkyl bond with DNA, e.g., cyclophosphamide), crosslinking agents (form two covalent bonds with DNA, e.g., cisplatin), or cleaving agents (cause DNA strand breaks, e.g., bleomycin A2, calicheamicin ?1).

Some of the most effective and widely used anticancer drugs today are known as TOPO poisons. They inhibit DNA-interactive enzymes known as topoisomerases (TOPO 1 and TOPO 2) which regulate the topology or 3D structure of DNA, e.g., doxorubicin, etoposide and irinotecan. These drugs induce TOPO-mediated DNA cleavage (breaks). Indeed DNA replication (the doubling up of DNA) which happens in the S (synthesis) phase of the cell cycle is the classical target of anticancer drugs. If a drug interferes with DNA function, then proteins and other biomolecules that are the downstream products of DNA, will also not be synthesized. Expectedly, the drugs are highly cytotoxic (cyto — meaning cells, so … toxic to cells), and kill cancer cells, as well as fast growing normal cells, e.g., cells of the bone marrow and gastrointestinal tract, and hair follicle cells, and cancer patients suffer the debilitating side effects of chemotherapy.

The M (mitosis or cell division) phase of the cell cycle is another effective target in cancer. (The cell cycle consists of the M phase — G1/G0 phase — S phase — G2 phase — M phase..) The ‘miracle’ drug taxol or paclitaxel, and the Vinca alkaloids (vincristine and vinblastine), are the best known potent inhibitors of mitosis. Mitosis involves ‘cytokinesis’ (when materials within the cell move), which results in the splitting of the nuclear material, i.e, the chromosomes containing the DNA, as well as the cytoplasm of the cell, into two daughter cells.

Cytokinesis involves the movement of several cytoskeletal proteins, such as tubulin which assembles (or polymerizes) and disassembles (depolymerizes) itself reversibly and continuously during cytokinesis. What taxol does is to bind tubulin irreversibly and inhibit tubulin depolymerization, while vinblastine inhibits tubulin polymerization. Before entering the S phase, the integrity of daughter cells is checked at the G1 phase, and before a cell enters the M phase, DNA integrity is checked at the G2 phase. When damage caused by the drugs is detected, a process known as apoptosis or PCD (programmed cell death) is triggered and the cells begin to die.

(To be continued)

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Gisela P. Padilla-Concepcion, PhD is a Professor of the Marine Science Institute and Chair, 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. Email her at: [email protected]