Castration-resistant prostate cancers still depend on nuclear androgen receptor (AR) function despite their lack of dependence on exogenous androgen. Second generation anti-androgen therapies are more efficient at blocking nuclear AR; however resistant tumors still develop. Recent studies indicate Src is highly active in these resistant tumors. By manipulating AR activity in several different prostate cancer cell lines through RNAi, drug treatment, and the use of a nuclear-deficient AR mutant, we demonstrate that androgen acting on cytoplasmic AR rapidly stimulates Src tyrosine kinase via a non-genomic mechanism. Cytoplasmic AR, acting through Src enhances laminin integrin-dependent invasion. Active Matriptase, which cleaves laminin, is elevated within minutes after androgen stimulation, and is subsequently shed into the medium. Matriptase activation and shedding induced by cytoplasmic AR is dependent on Src. Concomitantly, CDCP1/gp140, a Matriptase and Src substrate that controls integrin-based migration, is activated. However, only inhibition of Matriptase, but not CDCP1, suppresses the AR/Src-dependent increase in invasion. Matriptase, present in conditioned medium from AR-stimulated cells, is sufficient to enhance invasion in the absence of androgen. Thus, invasion is stimulated by a rapid but sustained increase in Src activity, mediated non-genomically by cytoplasmic AR, leading to rapid activation and shedding of the laminin protease Matriptase.

The localization of many photosensitizing agents has been attributed to distribution of low density lipoprotein (LDL)-bound drug as a function of the relative numbers of LDL receptors in different tissues. While the chlorin derivative NPe6 is a potent photosensitizing agent in the mouse, it binds mainly to mouse plasma high density lipoproteins (HDL) and albumin, with only 1% bound to LDL. This pattern suggests only a minor role for the LDL-receptor pathway with regard to N-aspartyl chlorin e6 (NPe6) biodistribution. Moreover, patterns of accumulation of radioactive NPe6, LDL and HDL in murine tissues are consistent with the suggestion that distribution of NPe6 to different tissues cannot be explained on the basis of an LDL-mediated mechanism.

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Plasma samples were obtained from 4 patients at intervals after administration of Photofrin II (2 mg/kg). Total porphyrin in plasma and protein/lipoprotein fractions was estimated after hydrolysis, and levels of different Photofrin II components were measured by HPLC. Pharmacokinetic data are provided relating to rates of loss of total porphyrin from plasma and to pool size and half-lives of sensitizers bound to albumin and lipoprotein fractions. Preferential persistence of the most hydrophobic components of Photofrin II was observed.