I was referring to that one and this one (sorry about formatting):
Abstract Number: 4596
Hypoxia increases potency of the proteasome inhibitor bortezomib (VelcadeTM, PS-341): Potential
for a hypoxic cell cytotoxin in solid tumors
Philipp Steiner, Hannah Neumeier, Melissa Pink, Kara Hoar, Fong-Ying Tsai, Joe Bolen, Julian Adams, Margaret
Read, Millennium Pharmaceuticals, Inc., Cambridge, MA.
The 26S proteasome is a ubiquitous enzyme that plays an essential role in the regulation of cellular protein degradation, gene
expression and cell cycle transition. In cancer cells these events can be deregulated and it has been hypothesized that
antagonism of proteasome function might provide therapeutic benefit. bortezomib (VelcadeTM, formerly known as PS-341), a
potent and selective inhibitor of the proteasome, induced apoptosis in a variety of human tumor cells and in pre-clinical cancer
animal models. In Phase I clinical trials, bortezomib demonstrated promising anti-tumor activity in multiple cancer types and is
now in Phase II and III trials. To understand the potential contribution of proteasome function to the observed biological
responses to treatment with bortezomib, we selected multiple myeloma cells to proliferate in high concentrations of the agent
and succeeded in generating stable cellular clones that demonstrated greater than 300-fold resistance. The parental and
bortezomib-resistant myeloma cell lines were subsequently grown as xenografts in mice to evaluate whether the in vitro
resistance translates into in vivo resistance. Surprisingly, bortezomib showed similar efficacy against tumors generated from both
cell populations, suggesting that the tumor microenvironment might influence the activity of bortezomib. One parameter
evaluated was the potential contribution of tumor hypoxia, a feature of rapidly growing solid tumors which is thought to
contribute to the clinical failure of many chemotherapeutics. We found the resistant cells to no longer be resistant to
bortezomib-induced apoptosis under hypoxic conditions in vitro. Importantly, the parental myeloma cells as well as human lung,
colon and renal tumor cells were more sensitive to bortezomib-induced apoptosis under similar hypoxic conditions. These
effects were specific for bortezomib, as other proteasome inhibitors and standard chemotherapeutic agents did not demonstrate
increased potency under hypoxic conditions. This raises the possibility that bortezomib might work in combination with
hypoxia-inducing anti-angiogenic agents in solid tumors. These findings suggest that bortezomib represents a novel class of
investigational agents for the treatment of solid tumors. <<
emphasis mine
Cheers, Tuck |
