A peptide-doxorubicin conjugate that selectively kills prostate tumour cells
is 15 times more potent than ordinary doxorubicin at blocking the growth of
prostate cancer, say researchers from the United States.
Dr Raymond Jones (Merck Research Laboratories, Pennsylvania) and colleagues
covalently linked doxorubicin with a peptide that is hydrolysed by prostate-specific
antigen (PSA) and found that, in the presence of prostate tumour cells secreting
PSA, the conjugate (L-377,202) was cleaved to release leucine-doxorubicin and
doxorubicin, both of which are cytotoxic compounds. To evaluate the effects
of the conjugate, the researchers administered it initially to human prostate
cancer cells in cell culture and then to nude mice with xenografts of human
prostate cancer. Doxorubicin and leucine-doxorubicin were used in the analyses
for comparison.
The weights of excised tumours for mice treated with the conjugate at doses
of 21.5, 14.3 and 7.2µmol/kg (doses that were below the maximum tolerated
dose — MTD — of the conjugate) were reduced by 87, 84 and 83 per cent,
respectively. In contrast, tumour weights for mice treated with leucine-doxorubicin
and doxorubicin, at their MTDs, were increased by 5 per cent and reduced by
6 per cent, respectively. The researchers also investigated whether the conjugate
had an improved therapeutic index relative to doxorubicin. They treated 11 groups
of 10 mice once a week for five consecutive weeks. At doses of doxorubicin above
its MTD, most of the mice died, despite a small reduction in tumour burden.
However, at higher molar doses of the conjugate no mice died and tumour weight
was reduced by approximately 90 per cent.
The researchers conclude that their peptide-doxorubicin conjugate, L-377,202,
could have better anti-tumour activity against prostate cancer with less toxicity
than conventional doxorubicin and would be useful in the treatment of hormone-refractory
prostate cancer (Nature Medicine 2000;6:1248).