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Berkovitch G, Doron D, Nudelman A, Malik Z, Rephaeli A: Novel multifunctional acyloxyalkyl ester prodrugs of 5-aminolevulinic acid display improved anticancer activity independent and dependent on photoactivation. J Med Chem. 2008 Dec 11;51(23):7356-69.
The metabolically released formaldehyde from the prodrugs was the dominant factor affecting cell viability by a ROS-dependent mechanism and was responsible for rapid phosphorylation of H2AX, suppression of the cell survival protein c-myc, and transient elevation in the expression of p21. 1a, which differs from 2a by releasing butyric instead of pivalic acid, was a more potent inducer of heme and acetylated H4 expression and induced apoptosis through activation of caspase 9. 1a and 1b specifically increased the level of the photosensitizer protoporphyrin 9, leading to enhancement of cell death by photodynamic therapy (PDT). |
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