The cytotoxicity of bleomycin may be better explained through its interactions
with RNA rather than as a result of DNA degradation, said Professor Sidney Hecht
(department of chemistry and biology, University of Virginia, US). Understanding
more about the real targets of this compound would enable the design of better
agents, he suggested.
Historically, the glycopeptide-derived antibiotic bleomycin had been assumed
to cause cell death via sequence dependent strand scission of DNA, said Professor
Hecht. However, it was now clear that all classes of RNA (messenger, transfer
and ribosomal) could be cleaved, some species with special specificity and efficiency.
RNA presented several attractive features as a therapeutic target, he suggested.
In addition to assuming a wide variety of structural forms, RNA, unlike DNA,
was found in the cell cytoplasm, it was not extensively packaged and it had
few associated repair mechanisms.
The aim now was to synthesise several bleomycin analogues that were specific
for either RNA or DNA, said Professor Hecht. However, the complexity of the
bleomycin molecule meant that such a synthesis would not be trivial. To overcome
this problem, his research group had begun to develop bead-based, solid-phase
synthesis to produce a library of bleomycin analogues. In various reaction mixtures,
each bead would carry a different analogue of bleomycin. From bead mixtures
immobilised on a matrix, individual molecules could be assayed using “beacon”
forms of DNA and RNA that fluoresced according to whether or not the substrate
had been cleaved. The assay had been validated substantially, including assessments
of the activity of the bead-linked bleomycin analogues and the use of truncated
forms of RNA as beacon species.