Narcissus and Daffodil

Pharmacology of Narcissus compounds 349
inhibit protein synthesis and prevent the growth of cancer cells and viruses
(see Figure 13.1).
During antiviral screening of medicinal plants from the Pacific area, Furasawa
and co-workers found that the alkaloid pretazettine was active against Rauscher
viral leukaemia and spontaneous T-cell leukaemia in mice (Furusawa et al., 1976b,
1979). Pretazettine was inhibitory towards murine retroviruses in cell cultures and
in vivo. The compound was shown to inhibit viral reverse transcriptase (Furasawa
et al., 1978), and was cytotoxic due to a specific inhibitory action on cellular
protein rather than nucleic acid synthesis and therefore active against non-viral
transplantable tumours. Later studies established that pretazettine was active
against Ehrlich ascites carcinoma – a non-viral, transplantable tumour – in mice
(Furusawa et al., 1981) and that the compound enhanced the antitumour activity
of a standard combination of adriamycin, 1,3-bis-(2-chloroethyl)-1-nitrosourea
(BCNU) and cyclophosphamide – the so-called ABC regimen – when used as an
adjuvant to the latter. Significant survival rates were seen in inoculated animals.
The authors also demonstrated that pretazettine could inhibit protein synthesis,
but not nucleic acid synthesis in human carcinoma cells in vitro. A further interesting
finding was that adriamycin pre-treated, human carcinoma cells were more
sensitive to pretazettine; therefore the drug could be used at lower doses which
were not inhibitory when pretazettine was used on its own. This suggested to
the authors that the compound might be useful as adjuvant therapy, eradicating
residual tumour cells by preventing the synthesis of proteins, notably DNA polymerase
beta, necessary for DNA repair.
In addition to the above, preliminary experiments suggested that pretazettine
was effective against intraperitoneally inoculated Lewis-lung carcinoma – another
non-viral, transplantable tumour – in mice (Furusawa and Furusawa, 1983). Pretazettine
was also studied when the inoculation was subcutaneous in singeneic
mice, more resistant to chemotherapy (Furusawa and Furusawa, 1986). In the
latter model, pretazettine was inhibitory to pulmonary metastases but not growth
of the primary tumour or in prolonging life span. The compound was more effective
against the primary tumour when combined with standard cytotoxic agents
such as adriamycin, cisplatin, 5-fluorouracil, methotrexate and vincristine; these
were not effective when administered individually. This indicates that pretazettine
may be useful as an adjuvant to induce positive effects from otherwise inactive
agents. In allogenic mice, pretazettine inhibited metastases and also prolonged life
span.
The same group has also investigated the activity of pretazettine against
spontaneous T-cell leukaemia in mice compared with that of some established
antileukaemic agents. The activity of pretazettine was shown to be superior to
methotrexate, 6-thioguanine and adriamycin, but inferior to vincristine. Combination
with vincristine, 6-thioguanine and adriamycin was synergistic whereas,
combination with methotrexate was not. Pretazettine was also shown to reverse the
leukaemia enhancing effect of cyclosporine in this animal model at the preleukaemic
stage, although the mechanism was unclear (Furusawa and Furusawa,
1988). The implications of this work for the treatment of similar cancers in man
await confirmation by independent study.
Pretazettine has been shown to be active against selected RNA-containing
flaviviruses (Japanese encephalitis, yellow fever and dengue) and bunyaviruses