AABRE: NETWORKING IN PUERTO RICO

PR-AABRE Researcher: Antonio Alegría, Ph.D., Department of Chemistry, UPR, Humacao Campus

Cluster: Drug Design and Delivery

Collaborators: Fernando González, Ph.D. (UPR, Río Piedras Campus); Beatriz Zayas, Ph.D. (Universidad Metropolitana); Rafael Arce, Ph.D.(UPR, RP); Carmelo García, Ph.D. (UPR, H)

Mentor: Nancy Oleinick, Ph.D. (Case Western School of Medicine)

Project Title: Photosensitized reduction and DNA alkylation of alkylating quinones and nitroarenes

CHEMISTRY PROFESSOR ANTONIO ALEGRÍA’S RESEARCH at the University of Puerto Rico in Humacao aims to improve Photodynamic Therapy (PDT), a new FDA-approved treatment for solid cancer tumors. PDT is a two-step procedure done on an outpatient basis that is relatively pain free and involves less risk than surgical procedures. “In this type of therapy, a nontoxic dye, the drug, is injected into the patient and after one to three days the patient is submitted to red light irradiation of the tumor.” The light “switches on” the dye, destroying cancerous cells without damaging healthy tissue surrounding the tumor.

“The dye has a preferential localization in the tumor—up to 20 times that of normal tissue—and is activated by the light to react with oxygen and form singlet oxygen, which actually burns the tumor tissue. The only side effect of this treatment is light sensitivity to skin and eyes for some days,” says Alegría.

However, most solid tumors have very little oxygen inside them and tumor elimination could be improved if other types of molecules—instead of oxygen—were activated. Also, the singlet oxygen that is produced will not travel to the inner sites of the tumor while burning the capillaries that surround the tumor. “Therefore, if the tumor is killed by PDT, it is mostly because of lack of oxygen and food inside tumor cells due to blood vasculature collapse and not to direct tumor damage. We think that a combination of dye and a bioalkylating compound, in addition to singlet oxygen, production could be more efficient in solid tumor cell killing than with singlet oxygen production alone.”

Alegría’s research team will test the dyes with bioalkylating compounds to induce tumor cell death. “First of all, we need to determine which couples of dye and bioalkylating compound are efficient in killing solid tumor cells. At present we have identified a dye and bioalkylating compound (an aziridinylquinone), which shows a very good yield of DNA covalent binding in vitro upon red light exposure. [DNA covalent binding is a lesion which, if not repaired promptly, could induce cell death.] Second, we need to understand why these promising couples behave well and under which environmental conditions.”

Testing is being done under both neutral and acidic conditions in the presence and absence of oxygen. Alegría’s research team studies the pH variation because couples which produce DNA covalent binding at acidic pH values are preferred (solid tumors are acidic). They also test oxygen concentration behavior because different degrees of oxygen exist in different sites of the tumor tissue.

Alegría would like to see couples of dye and bioalkylating compounds kill tumor cells in vitro and, in the future, kill implanted tumors in animals. Further work will be needed to determine which compound, dye, and light dosages make tumor ablation most effective.

ae_alegria@webmail.uprh.edu