Morphological characterisation of the cell-growth inhibitory activity of rooperol and pharmacokinetic aspects of hypoxoside as an oral prodrug for cancer therapy

Albrecht, C. F. ; Theron, E. J. ; Kruger, P. B. (1995)


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Hypoxoside is the major diglucoside isolated from the corms of the plant family Hypoxidaceae, It contains an. unusual E-pent-l-en-4-yne 5-carbon bridging unit with two distal catechol groups to which the glucose moieties are attached, It is non-toxic for BL6 mouse melanoma cells in tissue culture on condition that the fetal calf serum in the medium is heat-inactivated for 1 hour at 56°C in order to destroy endogenous beta-glucosidase activity. The latter catalyses hypoxoside conversion to its cytotoxic aglucone, rooperol, which, when tested as a pure chemical, caused 50% inhibition of BL6 melanoma cell growth at 10 μg/ml, Light and electron microscopy revealed that the cytotoxic effect of rooperol manifested as vacuolisation of the cytoplasm and formation of pores in the plasma membrane. Indications of apoptosis were also found. Pharmacokinetic studies on mice dosed intragastrically with hypoxoside showed that it was deconjugated by bacterial beta-glucosidase to form rooperol in the colon, Surprisingly, no hypoxoside or rooperol was detectable in the serum, Only phase II biotransformation products (sulphates and glucuronides) were present in the portal blood and bile, In contrast, however, in human serum after oral ingestion of hypoxoside, the metabolites can reach relatively high concentrations, Rooperol metabolites isolated from human urine were non-toxic for BL6 melanoma cells in culture up to a concentration of 200 μg/ml. In the presence of betaglucuronidase, which released rooperol from the metabolites, 50% growth inhibition was achieved at a 75 μg/ml metabolite concentration, The supernatant of a human melanoma homogenate could also cause deconjugation of the metabolites to form rooperol,It can be concluded from these findings that rooperol has promising properties as an oral prodrug for cancer therapy in humans given its complete first-pass metabolism into non-toxic conjugates which may be activated in tumours with high deconjugase activity, Rodent cancer models are, however, not applicable since rooperol metabolites are completely sequestered in the bile.

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