Administration of the aromatic polycyclic dione compounds hypericin or pseudohypericin to experimental animals provides protection from disease induced by retroviruses that give rise to acute, as well as slowly progressive, diseases. For example, survival from Friend virus-induced leukemia is significantly prolonged by both compounds, with hypericin showing the greater potency. Viremia induced by LP-BM5 murine immunodeficiency virus is markedly suppressed after infrequent dosage of either substance. These compounds affect the retroviral infection and replication cycle at least at two different points: (i) Assembly or processing of intact virions from infected cells was shown to be affected by hypericin. Electron microscopy of hypericin-treated, virusproducing cells revealed the production of particles containing immature or abnormally assembled cores, suggesting the compounds may interfere with processing of gag-encoded precursor polyproteins. The released virions contain no detectable activity of reverse transcriptase. (ii) Hypericin and pseudohypericin also directly inactivate mature and properly assembled retroviruses as determined by assays for reverse transcriptase and infectivity. Accumulating data from our laboratories suggest that these compounds inhibit retroviruses by unconventional mechanisms and that the potential therapeutic value of hypericin and pseudohypericin should be explored in diseases such as AIDS.We recently reported (1) that two naturally occurring polycyclic aromatic diones, hypericin and pseudohypericin, possess antiretroviral activity. The two compounds, which are derived from the plants of the Hypericum genus (St. Johnswort) (2-5), markedly suppress the spread of murine retrovirus infections both in vivo and in vitro (1). We have now compared the mechanisms of action and the therapeutic potentials of different doses of these agents in two murine retroviral systems. In the Friend virus system (6-8) the compounds can preclude the onset of acute Friend virusinduced erythroleukemia. In the other system a more slowly progressing, fatal form of murine immunodeficiency is induced by the LP-BM5 virus (9, 10); hypericin and pseudohypericin prevent development of significant viremia and minimize disease in mice infected with the LP-BM5 virus.

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SummaryThe mechanism of cell death induction by dimethyl tetrahydroxyhelianthrone (DTHe), a new second-generation photodynamic sensitizer, is analysed in human leukaemic cell lines in comparison with the structurally related hypericin. DTHe has a broad range of light spectrum absorption that enables effective utilization of polychromatic light. Photosensitization of HL-60 cells with low doses of DTHe (0.65 µM DTHe and 7.2 J cm -2 light energy) induced rapid apoptosis of ≥90% of the cells. At doses ≥2 µM, dying cells assumed morphological necrosis with perinucleolar condensation of chromatin in HL-60 and K-562 cell lines. Although nuclear fragmentation that is characteristic to apoptosis was prevented, DNA digestion to oligonucleosomes proceeded unhindered. Such incomplete apoptosis was more prevalent with the related analogue hypericin throughout most doses of photosensitization. Despite hypericin being a stronger photosensitizer, DTHe exhibited advantageous phototoxic properties to tumour cells, initiating apoptosis at concentrations about threefold lower than hypericin. Photosensitization of the cells induced dissociation of the nuclear envelope, releasing lamins into the cytosol. DTHe also differed from hypericin in effects exerted on the nuclear lamina, causing release of an 86-kDa lamin protein into the cytosol that was unique to DTHe. Within the nucleus, nuclear envelope lamin B underwent covalent polymerization, which did not affect apoptotic nuclear fragmentation at low doses of DTHe. At higher doses, polymerization may have been extensive enough to prevent nuclear collapse. Hut-78, CD4 + cells were resistant to the photodynamically activated apoptotic pathway. Beyond the tolerated levels of photodynamic damage, these cells died exclusively via necrosis. Hut-78 cells overexpress Bcl-X L as well as a truncated Bcl-X L tr isoform that could contribute to the observed resistance to apoptosis.Keywords: photodynamic therapy; hypericin; dimethyl tetrahydroxyhelianthrone; Bcl-X; Bax; lamin; apoptosis 423British Journal of Cancer (1999) 79(3/4), 423-432 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received Efforts to identify novel efficacious agents for photodynamic therapy led us to evaluate the photodynamically induced cytotoxicities of a newly designed photosensitizer 10,13-dimethyl 1,3,4,6-tetrahydroxyhelianthrone (DTHe) (Figure 1), in leukaemic cell lines. DTHe was chosen because of its dibenzperylenequinone chromophore (seven aromatic rings) that has absorption spectral properties virtually identical to hypocrellins, potent anti-tumoral photosensitizers isolated from the parasitic fungus Hypocrella bambuase which grows in China and Tibet (Diwu, 1990;Diwu, 1995; Miller, 1997). DTHe also shares structural similarities with HY and was anticipated to be a potent photosensitizer owing to its considerable light absorbance in the visible range of the spectrum. The phototoxicity profiles and mechanisms of cell death induction of DTHe were analysed in comparison with those of HY in HL-60, K-562 and Hut-...