texaphyrin and Ovarian-Neoplasms

In an effort to increase the stability and control the platinum reactivity of platinum-texaphyrin conjugates, two Pt(IV) conjugates were designed, synthesized, and studied for their ability to form DNA adducts. They were also tested for their anti-proliferative effects using wild-type and platinum-resistant human ovarian cancer cell lines (A2780 and 2780CP, respectively). In comparison to an analogous first-generation Pt(II) chimera, one of the new conjugates provided increased stability in aqueous environments. Using a combination of (1) H NMR spectroscopy and FAAS (flameless atomic-absorption spectrometry), it was found that the Pt(IV) center within this conjugate undergoes photoinduced reduction to Pt(II) upon exposure to glass-filtered daylight, resulting in an entity that binds DNA in a controlled manner. Under conditions in which the Pt(IV) complex is reduced to the corresponding Pt(II) species, these new conjugates demonstrated potent anti-proliferative activity in both test ovarian cancer cell lines.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; DNA; Drug Design; Female; Humans; Light; Organoplatinum Compounds; Ovarian Neoplasms; Ovary; Oxidation-Reduction; Porphyrins

In our effort to investigate further texaphyrin conjugation as a means of increasing delivery and accumulation of known anticancer platinum agents in cancer cells, we have continued our studies on the mode of action of a texaphyrin-platinum conjugate, particularly in cisplatin-resistant tumor cells that are characterized by several mechanisms of resistance, including reduced drug accumulation. Our results provide support for the proposal that intracellular platinum and Pt-DNA adduct levels were significantly increased using our conjugate relative to corresponding Pt controls. Moreover, no differences were found in cellular accumulation and Pt-DNA adduct formation between Pt sensitive and Pt resistant ovarian cells. As a result, resistance to the conjugate was lower than cisplatin in resistant cells. Based on these results we conclude that texaphyrin conjugation provides a promising strategy for overcoming biochemical pharmacologic mechanisms of resistance.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Humans; Organoplatinum Compounds; Ovarian Neoplasms; Porphyrins