Vol. 333 No.
26 SEMINARS IN MEDICINE OF THE BETH ISRAEL HOSPITAL, BOSTON
SEMINARS IN MEDICINE
OF THE
BETH ISRAEL HOSPITAL, BOSTON
JEFFREY S. FLIER, M.D., Editor
LISA H. UNDERHILL, Assistant Editor
CLINICAL APPLICATIONS OF RESEARCH ON
ANGIOGENESIS
JUDAH FOLKMAN, M.D.
A NGIOGENESIS is fundamental to reproduction, de-
velopment, and repair. All these processes depend
on the tightly regulated growth of blood vessels that
can “turn on” and “turn off” within a brief period. When
blood vessels grow unabated, angiogenesis becomes
pathologic and sustains the progression of many neoplas-
tic and non-neoplastic diseases. The realization that tu-
mor growth requires new blood vessels and the identifi-
cation of chemical factors that mediate angiogenesis have
broadened our understanding of pathologic processes
and opened new avenues to the diagnosis and treatment
of these diseases.
Tumor hypervascularity was initially thought to
reflect inflammatory vasodilation of preexisting host
vessels, a response to tumor metabolites and necrotic
tumor products that was of no benefit to the tumor (re-
viewed in reference 1). Another point of view was that
tumor growth and metastasis depend on angiogenesis
and that a chemical signal from tumor cells can shift
resting endothelial cells into a phase of rapid growth.2
These ideas were not widely accepted at first, but a clear
concept of the role of angiogenesis in cancer and other
diseases has now emerged.1
ANGIOGENESIS IN NEOPLASTIC DISEASE
Most tumors in humans persist in situ for months to
years without neovascularization but then become
vascularized when a subgroup of cells in the tumor
“switches” to an angiogenic phenotype.1 In the pre-
vascular phase, the tumor is rarely larger than 2 to 3
mm3 and may contain a million or more cells.1 Such
asymptomatic lesions are sometimes directly visible
on the skin or cervix or in the bladder, but usually
they are clinically undetectable. Cells in prevascular
tumors or dormant micrometastases may replicate as
From the Departments of Surgery and Cell Biology, Harvard Medical School;
and the Department of Surgery, Children’s Hospital — both in Boston. Address
reprint requests to Dr. Folkman at Children’s Hospital, Hunnewell 103, 300
Longwood Ave., Boston, MA 02115.
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1757
rapidly as those in expanding, vascularized tumors,
but without the growth of new vessels the rate of pro-
liferation of such cells reaches equilibrium with their
rate of death.3,4
The switch to the angiogenic phenotype involves a
change in the local equilibrium between positive and
negative regulators of the growth of microvessels.5 Tu-
mor cells may overexpress one or more of the positive
regulators of angiogenesis, may mobilize an angiogenic
protein from the extracellular matrix, may recruit host
cells such as macrophages (which produce their own
angiogenic proteins), or may engage in a combination
of these processes (as reviewed in reference 6). Of the
12 known angiogenic proteins1 (Table 1), those most
commonly found in tumors appear to be basic fibro-
blast growth factor (bFGF) and vascular endothelial
growth factor (also known as vascular permeability fac-
tor). The angiogenic activities of these two factors can
be synergistic.8
Up-regulation of an angiogenic factor is not suffi-
cient in itself for a tumor cell to become angiogenic,
however. Certain negative regulators or inhibitors of
vessel growth may need to be down-regulated.5 These
endogenous inhibitors are part of an extensive group of
suppressors (Table 2) that normally defends the vascu-
lar endothelium from mitogenic stimuli. More than a
trillion endothelial cells line the inside of blood vessels
and cover an area of approximately 1000 m2 in a 70-kg
adult.11 The turnover time of these normally quiescent
cells can exceed 1000 days.12 During angiogenesis, how-
ever, capillary endothelial cells can proliferate as rapid-
ly as bone marrow cells, which have a mean turnover
time of five days. Endothelial-cell proliferation can also
be regulated or restrained by pericytes (Antonelli-
Orlidge et al. and Satoh et al., reviewed in reference 1),
by the sequestration of potent mitogens in the extracel-
lular matrix,1 by changes in endothelial-cell shape that
reduce the sensitivity of the cells to growth factors (Ing-
ber, reviewed in reference 1), and by certain endothelial
integrins.13
At the cellular level, the onset of neovascularization
augments tumor growth through a “perfusion” effect
and a “paracrine” effect (Nicosia et al., Rak et al., and
Hamada et al., reviewed in reference 1) (Fig. 1). In a
crowded tissue, perfusion is more efficient than simple
diffusion in allowing nutrients and oxygen to enter and
catabolites to exit. The paracrine effect results from
the production of growth factors by endothelial cells
(for example, bFGF, insulin-like growth factor, platelet-
derived growth factor, and granulocyte colony-stim-
ulating factor) or their release by macrophages and
other host cells delivered by blood vessels to the tumor
(Fig. 1).
From a clinical perspective, neovascularization per-
mits tumors to grow and metastasize; it also heralds
the onset of symptoms. Most tumors become sympto-
matic and clinically detectable only after neovascular-
ization. It should be emphasized, however, that the
switch to the angiogenic phenotype does not always
1758 THE NEW ENGLAND JOURNAL OF MEDICINE Dec. 28, 1995

Table 1. Endogenous Angiogenic Factors. worldwide. Various forms of retinal

neovascularization in infants and
MOLECULAR ENDOTHELIAL YEAR
FACTOR WEIGHT MITOGEN* REPORTED AUTHORS† adults are thought to be triggered by
hypoxia in the area of the retina. Re-
Fibroblast growth factors
Basic 18,000 Yes 1984 Shing et al. cent evidence17,18 indicates that the
Acidic 16,400 Yes 1984 Maciag et al. angiogenic protein vascular endo-
1985 Esch et al. thelial growth factor19 is the chief
Angiogenin 14,100 No 1985 Fett et al.
mediator of this form of angiogene-
Transforming growth 5,500 Yes 1986 Schreiber et al.
factor a sis. Moreover, up-regulation of vas-
Transforming growth 25,000 No‡ 1986 Roberts et al. cular endothelial growth factor is a
factor b response to the local hypoxia20 pro-
Tumor necrosis factor a 17,000 No 1987 Fràter-Schröder et al., Leibovich duced in a tumor by vascular com-
et al.
Vascular endothelial growth 45,000 Yes 1983 Senger et al.,
pression and ischemia. The for-
factor 1989 Ferrara et al., Connolly et al., mation of collateral vessels in an
Plouet et al. ischemic heart or limb may involve a
Platelet-derived endothelial- 45,000 Causes DNA 1989 Ishikawa et al. similar process. Neovascularization
cell growth factor synthesis
Granulocyte colony-stimulating 17,000 Yes 1991 Bussolino et al.
in atherosclerotic plaques21 may also
factor be mediated by the overexpression
Placental growth factor 25,000 Weak 1991 Maglione et al. of vascular endothelial growth factor
Interleukin-8 40,000 Yes 1992 Koch et al. and by local hypoxia22 and may con-
Hepatocyte growth factor 92,000 Yes 1993 Rosen et al., Bussolino et al. tribute to the growth and rupture of
Proliferin 35,000 Yes 1994 Jackson et al.7 the plaque. In hemangiomas of in-
*As measured in vitro. fancy, the expression of both vascu-
†Except for reference 7, complete citations can be found in reference 1. lar endothelial growth factor and
‡This factor inhibits endothelial proliferation in vitro, but a focal injection in vivo stimulates angiogenesis. bFGF is excessive during the prolif-
erative phase (Takahashi et al., re-
result in a rapidly proliferating tumor. Certain tumors, viewed in reference 1) but decreases toward normal lev-
such as adrenal adenoma, do not have growth that els during the involuting phase. In an experimental
corresponds to their high rate of angiogenic activity. model of rheumatoid arthritis, excessive production of
Certain thin melanomas may actually regress at the angiogenic factors from infiltrating macrophages, im-
time of neovascularization, possibly because of the in- mune cells, or inflammatory cells may mediate the in-
hibitory effect of endothelium-derived interleukin-6.14 growth of a vascular pannus in a joint.23
Moreover, in distant metastases angiogenesis may be In patients with psoriasis, hypervascular skin lesions
suppressed by circulating inhibitors from a primary overexpress the angiogenic polypeptide interleukin-8
tumor and may become apparent only after its remov- and underexpress the inhibitor of angiogenesis, throm-
al.3,4,15 bospondin-1.24 (Although the hypervascularity in psoria-
Paradoxically, neovascularization gradually reduces sis is usually attributed to classic angiogenesis, the in-
a tumor’s accessibility to chemotherapeutic drugs. Tu- creased elongation and widening of dermal vessels in
mors do not outgrow their blood supply but instead these patients may be a form of “nonsprouting” angio-
compress it. Tumors in the earliest stages of neovascu- genesis.25) Peptic ulcers in animals appear to be deficient
larization (those smaller than 1 cm3) are usually well in microvessels in the ulcer bed.26 In gastric ulcers in hu-
perfused. By the time they are clinically detectable, mans, the level of the angiogenic protein bFGF is 23
however, increased interstitial pressure from leaky ves- times lower than in normal mucosa.27 Furthermore, oral
sels in the tumor (Brown et al., reviewed in reference administration of acid-stable fibroblast growth factor in-
1), in the relative absence of intratumor lymphatics duces angiogenesis in the ulcer bed and accelerates the
( Jain et al., reviewed in reference 1), causes vascular healing of ulcers in animals,26 a finding that has led to
compression and eventually central necrosis. Thus, it is the development of clinical trials.27,28 Certain phases of
not surprising that in rodents antiangiogenic therapy reproduction, such as ovulation, repair of the menstruat-
increases the delivery of chemotherapy to a tumor,16 ing uterus, and development of the placenta, depend on
probably by lowering interstitial pressure and unpack- physiologic angiogenesis.29 Dysfunction of endogenous
ing the mass of tumor cells. angiogenic stimulators or inhibitors may underlie several
female reproductive disorders, such as prolonged men-
ANGIOGENESIS IN NON-NEOPLASTIC DISEASE strual bleeding and infertility. Developmental disorders
The term “angiogenic disease”1 refers to underlying such as bowel atresia, vascular malformations, hemangi-
conditions dominated by the abnormal growth of mi- omas, and unilateral facial atrophy may arise from ab-
crovessels — angiogenesis that is either excessive or normal vascular development, through defects in either
deficient. An important example of such a disease is angiogenesis (the sprouting of vessels from preexisting
ocular neovascularization, a major cause of blindness vessels) or vasculogenesis (the appearance of new ves-

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Vol. 333 No. 26 SEMINARS IN MEDICINE OF THE BETH ISRAEL HOSPITAL, BOSTON 1759

sels) (Millauer et al., reviewed in ref- Table 2. Endogenous Negative Regulators of Endothelial-Cell Proliferation.*
erence 1).
INHIBITS INHIBITS IS IN THE IS IN THE EXTRA-
FACTOR PROLIFERATION CHEMOTAXIS CIRCULATION CELLULAR MATRIX AUTHORS†
CLINICAL APPLICATIONS
Platelet factor 4 Yes Yes Yes No Sharpe et al., Taylor
Clinical applications of research and Folkman
on angiogenesis have taken three Thrombospondin-1 Yes Yes Yes Yes Rastinejad et al., Iruela-
directions: the quantitation of an- Arispe et al.
giogenesis for use in diagnosis and Tissue inhibitors of Murphy et al.,
metalloprotein- Moses et al.
prognosis, the acceleration of angio- ases (TIMP)
genesis during repair, and the inhi- TIMP-1 No Yes Yes Unknown
bition of angiogenesis. TIMP-2 Yes Yes Yes Unknown
TIMP-3 Unknown Unknown Unknown Yes
Diagnostic and Prognostic Prolactin (16-kd Yes Yes — — Clapp et al.9
fragment)
Applications
Angiostatin (38-kd Yes Yes Yes — O’Reilly et al.
The quantitation of angiogenesis fragment of
plasminogen)
in a biopsy specimen when cancer is bFGF soluble receptor Yes — Yes — Hanneken et al.10
diagnosed may help predict the risk Transforming growth Yes Yes Yes — Roberts et al., Baird et
of metastasis or recurrence. Quanti- factor b al., Muller et al.
tation of microvessel density in his- Interferon alfa Yes Yes Yes — Sidky et al.
tologic specimens of invasive breast Placental proliferin- Yes Yes Yes — Jackson et al.7
related protein
cancer, for example, has provided
an indication of the risk of metasta- *The bFGF soluble receptor has not been tested in vivo as an inhibitor of angiogenesis. All the other factors shown inhibit
sis.30 Multivariate analysis showed angiogenesis in vivo except transforming growth factor b.
†Except for references 7, 9, and 10, complete citations can be found in reference 1.
that the density of microvessels in
patients with lymph-node–negative
breast cancer was a better predictor of metastasis than brospinal fluid correlated with the density of microves-
tumor grade, tumor size, estrogen-receptor positivity, or sels in histologic sections, a correlation that itself pro-
other prognostic markers (Weidner et al., reviewed in vided a prognostic indication of the risk of death.
reference 1). This result has been confirmed independ- In infants with hemangiomas, urinary bFGF levels
ently in several centers and in a five-year prospective are also abnormally elevated and return toward normal
study. A positive association between tumor angiogene- with involution of the lesions. In life-threatening he-
sis and the risk of metastasis, tumor recurrence, or death mangiomas treated with interferon alfa-2a, as described
has also been reported with regard to various other types below, the quantitation of urinary bFGF has been useful
of tumors. Most published reports have demonstrated an in determining an effective dose and differentiating be-
association between angiogenesis and outcome (reviewed tween hemangioma and vascular malformation (unpub-
in reference 31). lished data).
Perhaps high microvessel density is a successful pre-
dictor of metastatic risk because high density increases Therapeutic Acceleration of Angiogenesis
the area of the vascular surface, facilitating the escape Preclinical studies in which orally administered bFGF
of tumor cells into the circulation. An angiogenic cell was shown to stimulate angiogenesis and to accelerate
shed from a primary tumor is more likely than a nonan- the healing of duodenal ulcers in rats26 have prompted
giogenic cell to develop into a detectable metastasis. the initiation of phase 1 clinical trials to evaluate this
Tumor cells that are not angiogenic may become dor- therapy in patients with gastric27 or duodenal28 ulcers
mant micrometastases until they themselves eventually refractory to conventional therapy. In one such study,
switch to the angiogenic phenotype (Fig. 2). orally administered bFGF was found to heal gastric ul-
An indirect measure of angiogenic activity in certain cers caused by nonsteroidal antiinflammatory drugs.27
patients with tumors or non-neoplastic diseases may be These clinical studies suggest that angiogenic and
the quantitation of angiogenic proteins in body fluids. other growth factors have a role in healing gastrointes-
High concentrations of bFGF were found in the serum tinal ulceration. On a weight-for-weight basis, bFGF is
of approximately 10 percent of a wide range of patients almost 1 million times more potent than the histamine
with cancer (Watanabe et al., reviewed in reference 1) H2 blocker cimetidine in healing duodenal ulcers in ro-
and in the urine of more than 37 percent of such pa- dents; bFGF does not reduce the level of gastric acid.
tients.33 Although the ability of bFGF to heal peptic ulcers
Concentrations of biologically active bFGF were could depend on its mitogenicity (observed in vitro),
abnormally high in the cerebrospinal fluid of children most in vivo studies of fibroblasts, smooth-muscle
with brain tumors, but not in children with hydro- cells, and endothelial cells show that the predominant
cephalus or malignant disease outside the central effect of this protein is to stimulate intense angiogene-
nervous system.34 The concentration of bFGF in cere- sis. It is interesting to note that the antiulcer drug su-

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1760 THE NEW ENGLAND JOURNAL OF MEDICINE Dec. 28, 1995

Tumor

Nutrients and Oxygen Endothelial cells

Supplied by Perfusion

Paracrine Growth Factors

(from endothelial cells)

Arteriole

Venule

Figure 1. Promotion of Tumor Growth by Neovascularization and Resulting Increases in Perfusion and Production of Paracrine
Growth Factors.
After neovascularization, tumors are perfused, and the entry of nutrients and exit of waste catabolites become more efficient. In
addition, tumor cells are stimulated in a paracrine fashion by the following growth factors produced by capillary endothelial cells:
fibroblast growth factors, heparin-binding epithelial growth factor, granulocyte colony-stimulating factor, platelet-derived growth fac-
tor, and insulin-like growth factor I. (Adapted from reference 1 with the permission of the publisher.)

cralfate (sucrose aluminum sulfate, or Carafate), ap-
pears to act by protecting endogenous mucosal bFGF
from degradation by acid.
Therapeutic Inhibition of Angiogenesis
Interferon Alfa-2a to Treat Life-Threatening or Sight-
Threatening Hemangiomas
Hemangiomas occur in 1 in 100 neonates35 and in
1 in 5 premature infants with birth weights below 1000 g.
These tumors grow rapidly in the first year of life (the
proliferating phase), slow down during the next five
years (the involuting phase), and gradually regress by
the age of 10 to 15 (the involuted phase). Most do not
need treatment. However, approximately 10 percent
cause serious tissue damage, interfere with a vital or-
gan, or become life-threatening. Such hemangiomas
can obstruct the airway, produce high-output heart
failure, or cause the Kasabach–Merritt syndrome, a
platelet-trapping thrombocytopenic coagulopathy that
is itself associated with a mortality rate of 30 to 50
percent. Hepatic hemangiomas have a mortality rate
of 30 to 50 percent (Enjolras et al., reviewed in refer-
ence 1). Approximately 30 percent of hemangiomas re-
spond dramatically to corticosteroid therapy and be-
gin to regress within a week. Forty percent respond
equivocally, and 30 percent do not respond at all1; in
rare cases, hemangiomatous growth is accelerated by
such therapy. When corticosteroids fail, there are no
dependable, safe, and effective alternatives for treating
life-threatening hemangiomas, although there are an-
ecdotal reports of favorable outcomes with radiation
(Schild et al., reviewed in reference 1), cyclophospha-
mide treatment (Hurwitz et al., reviewed in reference
1), and embolization (Argenta et al., reviewed in refer-
ence 1).
Laboratory studies indicating that interferon alfa-2a
could be antiangiogenic led to its successful use in
treating a life-threatening pulmonary hemangioma in
a seven-year-old child.36 With a few exceptions, the re-
sults of other case studies with interferon alfa-2a have
also been encouraging.1 In a study of infants and chil-
dren with life-threatening or sight-threatening heman-
giomas or large tissue-destructive hemangiomas, my
colleagues and I found that therapy with interferon
alfa-2a accelerated the regression of tumors in 18 of 20
patients.37
Although most infants treated with interferon alfa-
2a gain weight and grow normally, spastic diplegia has

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Vol. 333 No. 26 SEMINARS IN MEDICINE OF THE BETH ISRAEL HOSPITAL, BOSTON 1761

Figure 2. The Development of Heterogeneity in the Angiogenic

Phenotypes in a Primary Tumor and Its Relation to Whether Me-
tastases Are Clinically Detectable. In situ carcinoma
A neovascularized tumor may contain subgroups of cells that
display the angiogenic phenotype (dark tumor cells), as well as
cells that do not (light tumor cells). In a primary tumor, the areas
with the highest density of microvessels contain the cells that
are more likely to disseminate systemically. These metastatic
cells are also more likely to express the angiogenic phenotype
than cells escaping from areas with fewer microvessels. Tumor Angiogenic clone
cells that do not express the angiogenic phenotype may become
dormant micrometastases. In contrast, angiogenic tumor cells
may produce rapidly growing, clinically detectable metastases.
Breakdown of the basement membrane and microinvasion (for
example, around a breast duct containing carcinoma) have been Blood
supply
observed with and without neovascularization (both shown
here). (Adapted from reference 32 with the permission of the
publisher.)

Microinvasion
been reported in some children receiving interferon.
Therefore, my colleagues and I advise a neurologic and Neovascularization and
developmental evaluation before the start of interferon growth of tumor
therapy, and periodic assessment during and after ther-
apy. Combining corticosteroids and interferon alfa-2a
has no advantage and may increase toxic effects. Inter-
feron alfa-2a should not be used to treat vascular mal-
formations (sometimes called “cavernous hemangi-
omas”).
Interferon alfa-2a suppresses the production of fi-
broblast growth factors in human tumor cells.38 This
action could account for the efficacy of the drug against
hemangioma, because bFGF is one of the angiogenic
proteins overexpressed by hemangiomas (Takahashi et
al., reviewed in reference 1).
Ocular Neovascularization Metastasis
Thalidomide,39 administered orally, is now being
evaluated in a phase 2 clinical trial for the treatment
of patients with retinal neovascularization due to mac-
ular degeneration. Patients with macular degeneration
are also being treated with interferon alfa-2a adminis-
tered subcutaneously in a phase 3 clinical trial in 50
medical centers in the United States and Europe (Ada-
mis A: personal communication).
Arthritis
Although inhibitors of angiogenesis have not been
studied in a clinical trial in patients with arthritis, mi-
nocycline,40 a locally effective inhibitor of angiogenesis
that potentiates other such inhibitors when adminis-
tered systemically,16 has recently shown efficacy in such
patients.41 TNP-470 (also known as AGM-470) is a po-
tent inhibitor of the vascular pannus in experimental
arthritis.23
Cancer
Nine different inhibitors of angiogenesis are currently
being studied in phase 1 or 2 clinical trials as treatment
for a wide spectrum of solid tumors, including breast, co-
lon, lung, and prostate cancer, as well as Kaposi’s sarco-
ma.1 One of these drugs, TNP-470, a synthetic analogue

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Copyright © 1995 Massachusetts Medical Society. All rights reserved.
1762 THE NEW ENGLAND JOURNAL OF MEDICINE
of fumagillin,42 has been approved by the Food and Drug
Administration for phase 1 testing in many patients with
solid tumors. Other inhibitors of angiogenesis currently
in clinical trials in patients with advanced cancer include
platelet factor 443; carboxyaminotriazole44; BB-94 and
BB-2516, metalloproteinase inhibitors45,46; the sulfated
polysaccharide tecogalan (DS-4152)47; thalidomide39; in-
terleukin-1248; and linomide.49
General Principles of Antiangiogenic Therapy
Preclinical studies and clinical trials of antiangiogen-
ic therapy, including the treatment of hemangioma
with interferon alfa-2a, suggest guidelines for such ther-
apy that may be useful in the future care of patients
with cancer. First, antiangiogenic therapy is mainly di-
rected at small foci of migrating and proliferating endo-
thelial cells in capillaries at a site of angiogenesis. Thus,
a specific inhibitor of angiogenesis is not likely to cause
bone marrow suppression, gastrointestinal symptoms,
or hair loss. This is not to say that such a drug has no
other actions and no side effects.
Second, it appears that antiangiogenic therapy needs
to be administered for several months to a year or more.
Inhibitors of angiogenesis generally down-regulate neo-
vascularization by inhibiting the proliferation and mi-
gration of endothelial cells rather than by killing the
cells. The regression or involution of a vigorously grow-
ing capillary bed is a slower process than the lysis of tu-
mor cells. In the design of clinical trials it may therefore
be necessary to administer inhibitors of angiogenesis for
longer uninterrupted periods than is usual with conven-
tional cytotoxic agents.
Resistance to inhibitors of angiogenesis has not been
a major problem in long-term studies in animals or
clinical trials to date. Resistance to the drug did not de-
velop in babies with large hemangiomas of the medi-
astinum or liver who were treated with interferon alfa-
2a daily for up to a year.
Furthermore, a combination of antiangiogenic and
cytotoxic therapy may be more effective than either
type alone. In animals with tumors such combinations
can be curative, whereas the effect of either agent alone
is merely inhibitory.16 An inhibitor of angiogenesis such
as TNP-470 can substantially decrease DNA synthesis
in endothelial cells in a tumor bed, whereas cytotoxic
agents such as doxorubicin and cisplatin do not (Yama-
moto et al., reviewed in reference 1). These results sug-
gest that therapy directed against both the endothelial-
cell and the tumor-cell compartments of a tumor is
more effective than therapy given only against tumor
cells. Radiotherapy is also potentiated by antiangiogenic
therapy in tumor-bearing animals, partly because anti-
angiogenic therapy decreases hypoxia in the tumor.16
Finally, inhibitors of angiogenesis do not have to
cross the blood–brain barrier.
FUTURE DIRECTIONS
How will inhibitors of angiogenesis be used in med-
ical practice? Preclinical studies suggest two roles for
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Copyright © 1995 Massachusetts Medical Society. All rights reserved.
Dec. 28, 1995
them in the treatment of patients with cancer, regard-
less of tumor type. Such inhibitors could be used to po-
tentiate conventional chemotherapy and radiothera-
py,16 and after conventional therapy, when patients
enter a remission, they might maintain metastases in a
microscopic, dormant state (one analogous to the pres-
ence of infection without disease). Such “dormancy
therapy” has already been tested in animals that have
continued to have excellent health despite the presence
of dormant micrometastases in their lungs.4,15
The possibility of antiangiogenic gene therapy
against cancer is no longer far-fetched. Preliminary ex-
periments reveal that transfecting tumor cells with a
complementary DNA for angiostatin can suppress tu-
mor growth (Cao Y: personal communication). The
use of antitumor gene therapy with thrombospondin-1
has recently been reported in animals.50 For non-neo-
plastic ophthalmologic, dermatologic, and rheumato-
logic diseases characterized by angiogenesis, in which
prolonged suppression of pathologic neovasculariza-
tion is needed, inhibitors of angiogenesis are likely to
find wide use, especially because of their relatively low
level of toxicity.
The essential lesson from the preclinical and clini-
cal studies conducted so far is that the pathologic an-
giogenesis that contributes to joint destruction, blind-
ness, the rupture of a neovascularized atherosclerotic
plaque, or the lethality of a tumor appears to involve
a similar process in each disease, with only small vari-
ations in the regulation of the molecules mediating it.
I am indebted to the following colleagues for reading the manu-
script and for helpful suggestions: Anthony Adamis, Patricia D’Amore,
Joyce Bischoff, Noel Bouck, Yihai Cao, Robert D’Amato, Donald Ing-
ber, Michael Klagsbrun, Elise Kohn, and Bruce Zetter.
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