Therapeutic potentials of
angiostatin in the treatment of
cancer.
Laboratory of Angiogenesis Research,
Microbiology and Tumor Biology Center,
Karolinska Institute, S-171 77, Stockholm,
Sweden. yihai.cao@mtc.ki.se
The discovery of specific endothelial
inhibitors such as angiostatin and endostatin
not only increases our understanding of the
functions of these molecules in the regulation
of physiological and pathological
angiogenesis, but also provides an important
therapeutic strategy for cancer treatment.
Recent studies have demonstrated that the
angiostatin protein significantly suppresses
the growth of a variety of tumors in mice.
However, the dosages of angiostatin protein
used in these animal studies seem to be too
high for clinical trials. In addition,
repeated injections and long-term treatment
with angiostatin are required to reach its
maximal antitumor effect. In this article, I
will discuss several alternative approaches
that may become feasible to move angiostatin
therapy from animal experiments into the
clinic. In particular, I will emphasize the
therapeutic potentials of angiostatin gene
therapy and more potent angiogenesis
inhibitors that are related to
angiostatin.
Annu Rev Med, 1998, 49:, 407-24
Angiogenesis and tumor
metastasis.
Zetter BR Children's Hospital, Harvard
Medical School, Boston, Massachusetts 02115,
USA. zetter@a1.tch.harvard.edu
Angiogenesis, the recruitment of new blood
vessels, is an essential component of the
metastatic pathway. These vessels provide the
principal route by which tumor cells exit the
primary tumor site and enter the circulation.
For many tumors, the vascular density can
provide a prognostic indicator of metastatic
potential, with the highly vascular primary
tumors having a higher incidence of metastasis
than poorly vascular tumors. Tumor
angiogenesis is regulated by the production of
angiogenic stimulators including members of
the fibroblast growth factor and vascular
endothelial growth factor families. In
addition, tumors may activate angiogenic
inhibitors such as angiostatin and endostatin
that can modulate angiogenesis both at the
primary site and at downstream sites of
metastasis. The potential use of these and
other natural and synthetic angiogenic
inhibitors as anticancer drugs is currently
under intense investigation. Such agents may
have reduced toxicity and be less likely to
generate drug resistance than conventional
cytotoxic drugs. Clinical trials are now
underway to develop optimum treatment
strategies for antiangiogenic agents.
Nat Med, 1996 Jun, 2:6, 689-92
Angiostatin induces and sustains
dormancy of human primary tumors in
mice.
OReilly MS; Holmgren L; Chen C; Folkman J
Department of Surgery, Children's Hospital,
Boston, Massachusetts, USA.
There is now considerable direct evidence
that tumor growth is angiogenesis-dependent.
The most compelling evidence is based on the
discovery of angiostatin, an angiogenesis
inhibitor that selectively instructs
endothelium to become refractory to angiogenic
stimuli. Angiostatin, which specifically
inhibits endothelial proliferation, induced
dormancy of metastases defined by a balance of
apoptosis and proliferation. We now show that
systemic administration of human angiostatin
potently inhibits the growth of three human
and three murine primary carcinomas in mice.
An almost complete inhibition of tumor growth
was observed without detectable toxicity or
resistance. The human carcinomas regressed to
microscopic dormant foci in which tumor cell
proliferation was balanced by apoptosis in the
presence of blocked angiogenesis. This
regression of primary tumors without toxicity
has not been previously described. This is
also the first demonstration of dormancy
therapy, a novel anticancer strategy in which
malignant tumors are regressed by prolonged
blockade of angiogenesis.
Nat Biotechnol 1999
Apr;17(4):343-8
Systemic inhibition of tumor
growth and tumor metastases by intramuscular
administration of the endostatin
gene.
Blezinger P, Wang J, Gondo M, Quezada A,
Mehrens D, French M, Singhal A, Sullivan S,
Rolland A, Ralston R, Min W GeneMedicine,
Inc.,
The Woodlands, TX 77381-4248, USA.
Tumors require ongoing angiogenesis to
support their growth. Inhibition of
angiogenesis by production of angiostatic
factors should be a viable approach for cancer
gene therapy. Endostatin, a potent angiostatic
factor, was expressed in mouse muscle and
secreted into the bloodstream for up to 2
weeks after a single intramuscular
administration of the endostatin gene. The
biological activity of the expressed
endostatin was demonstrated by its ability to
inhibit systemic angiogenesis. Moreover, the
sustained production of endostatin by
intramuscular gene therapy inhibited both the
growth of primary tumors and the development
of metastatic lesions. These results
demonstrate the potential utility of
intramuscular delivery of an antiangiogenic
gene for treatment of disseminated
cancers.
Cell, 1997 Jan, 88:2, 277-85
Endostatin: an endogenous
inhibitor of angiogenesis and tumor
growth.
OReilly MS; Boehm T; Shing Y; Fukai N;
Vasios G; Lane WS; Flynn E; Birkhead JR; Olsen
BR; Folkman J
Department of Surgery, Children's Hospital,
Boston, Massachusetts 02115, USA
We previously identified the angiogenesis
inhibitor angiostatin. Using a similar
strategy, we have identified endostatin, an
angiogenesis inhibitor produced by
hemangioendothelioma. Endostatin is a 20 kDa
C-terminal fragment of collagen XVIII.
Endostatin specifically inhibits endothelial
proliferation and potently inhibits
angiogenesis and tumor growth. By a novel
method of sustained release, E. coli-derived
endostatin was administered as a nonrefolded
suspension. Primary tumors were regressed to
dormant microscopic lesions.
Immunohistochemistry revealed blocked
angiogenesis accompanied by high proliferation
balanced by apoptosis in tumor cells. There
was no toxicity. Together with angiostatin
data, these findings validate a strategy for
identifying endogenous angiogenesis
inhibitors, suggest a theme of fragments of
proteins as angiogenesis inhibitors, and
demonstrate dormancy therapy.
J Clin Invest, 1998 Mar, 101:5,
1055-63
Expression of angiostatin cDNA in
a murine fibrosarcoma suppresses primary tumor
growth and produces long-term dormancy of
metastases.
Cao Y; OReilly MS; Marshall B; Flynn E; Ji
RW; Folkman J
Laboratory of Angiogenesis Research,
Microbiology and Tumor Biology Center,
Karolinska Institute, S-171 77, Stockholm,
Sweden. yihai.cao@mtc.ki.se
Tumor growth and metastasis are
angiogenesis dependent. Previously, we
reported that angiostatin, a potent
angiogenesis inhibitor, produced by a primary
Lewis lung carcinoma suppressed its growth of
lung metastases (O'Reilly, M.S., L. Holmgren,
Y. Shing, C. Chen, R.A. Rosenthal, M. Moses,
W.S. Lane, Y. Cao, E.H. Sage, and J. Folkman.
1994. Cell. 79:315-328). Now we show that a
shift of balance of tumor angiogenesis by gene
transfer of a cDNA coding for mouse
angiostatin into murine T241 fibrosarcoma
cells suppresses primary and metastatic tumor
growth in vivo. Implantation of stable clones
expressing mouse angiostatin in C57Bl6/J mice
inhibits primary tumor growth by an average of
77%. After removal of primary tumors, the
pulmonary micrometastases in approximately 70%
of mice remain in a microscopic dormant and
avascular state for the duration of the
experiments, e.g., 2-5 mo. The tumor cells in
the dormant micrometastases exhibit a high
rate of apoptosis balanced by a high
proliferation rate. Our study, to our
knowledge, for the first time shows the
diminished growth of lung metastases after
removal of the primary tumor, suggesting that
metastases are self-inhibitory by halting
angiogenesis. Our data may also provide a
novel approach for cancer therapy by
antiangiogenic gene therapy with a specific
angiogenesis inhibitor.
Cancer Res 1999 Jul
15;59(14):3308-12
Liposomes complexed to plasmids
encoding angiostatin and endostatin inhibit
breast cancer in nude mice.
Chen QR, Kumar D, Stass SA, Mixson AJ
Department of Pathology and Greenebaum Cancer
Center, University of Maryland, Baltimore
21201, USA.
Gene therapy transfer of angiostatin and
endostatin represents an alternative method of
delivering angiogenic polypeptide inhibitors.
We examined whether liposomes complexed to
plasmids encoding angiostatin or endostatin
inhibited angiogenesis and the growth of
MDA-MB-435 tumors implanted in the mammary fat
pads of nude mice. We determined that plasmids
expressing angiostatin (PCI-Angio) or
endostatin (PCI-Endo) effectively reduced
angiogenesis using an in vivo Matrigel assay.
We then investigated the efficacy of these
plasmids in reducing the size of tumors
implanted in the mammary fat pad of nude mice.
Both PCI-Angio and PCI-Endo significantly
reduced tumor size when injected
intratumorally (P < 0.05). Compared to the
untreated control group, the mice treated with
PCI-Angio and PCI-Endo exhibited a reduction
in tumor size of 36% and 49%, respectively. In
addition, we found that i.v. injections of
liposomes complexed to PCI-Endo reduced tumor
growth in the nude mice by nearly 40% when
compared to either empty vector (PCI) or
untreated controls (P < 0.05). These
findings provide a basis for the further
development of nonviral delivery of
antiangiogenic genes.
Cancer Res, 1997 Dec, 57:23,
5277-80
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