ARTICLE
Auteur(s) : Daniel E
Gomez, Giselle V Ripoll, Santiago Girón, Daniel F Alonso
Laboratory of Molecular Oncology, Department of Science and
Technology Quilmes National University, R. Saenz Peña 180, Bernal
(1876), Buenos Aires, Argentina
Desmopressin (DDAVP, 1-deamino-8-D-arginine vasopressin) is a
synthetic analogue of the antidiuretic hormone vasopressin (( figure 1 )). Upon
homocysteine deamination in position 1 the antidiuretic effect is
prolonged and the substitution of L-arginine for D-arginine in
position 8 decreases the pressor effect of the molecule. After an
i.v. dose of 2-20 μg, the half life is between 50 and 158 min.
When administered intranasally, the half life is 90 min.
Although DDAVP is absorbed orally, the doses needed to reach an
antidiuretic effect are much higher than the ones needed i.v.
Metabolization of DDAVP is carried out in the liver and kidney but
is slower than for vasopressin. Approximately 60 % of the drug
is released by the kidney without metabolization. [1]. Some
patients treated in a repetitive way with short periods between
doses present a progressive decrease in the response. This is
probably related with a negative feed-back in the receptors of
endothelial cells [2].
Biological effects
In contrast to vasopressin, which binds to different cell membrane
receptors (V1a, V1b, V2, V3), DDAVP is a selective agonist for the
V2 receptor. This vasopressin receptor subtype is expressed in the
kidney collecting duct, and also mediates the antidiuretic effect
of the hormone in endothelial cells [3], mediating most of the non
renal effects of DDAVP. In the kidney collecting duct, DDAVP
activating the V2R causes water retention by inducing the
translocation of the water channel aquaporin-2 from intracellular
stores to the apical plasma membrane, an example of cAMP-mediated
exocytosis [4].
Von Willebrand factor (VWF) is a large glycoprotein playing a
role in primary haemostasis, by mediating adhesion of platelets to
the subendothelium. It also functions as a carrier protein for
coagulation factor VIII (FVIII), protecting it from proteolytic
degradation. VWF is synthesized in endothelial cells and
megakaryocytes as a precursor, pro-VWF. This precursor undergoes
dimerization, glycosylation, proteolytic cleavage into VWF and a
propeptide and assembly of the dimers into large multimers
(500-15,000 kDa). Multimerized VWF, along with equimolar amounts of
propeptide, is stored in specialized secretory granules named
Weibel-Palade bodies (WPB) [3]. DDAVP-induced VWF secretion results
from V2R-mediated, cAMP-dependent exocytosis from WPBs.
The profibrinolytic role of DDAVP was one of its first effects
to be described. This profibrinolytic activity is due to an
increase in tissue plasminogen activator (tPA), the enzyme that
converts plasminogen to plasmin and thus initiates fibrin
degradation. The vascular endothelium is thought to be the main
source of plasmatic tPA. In cultured endothelial cells, tPA is
expressed at low levels. Its synthesis is up-regulated, usually at
the transcriptional level, in response to fluid shear stress,
thrombin, histamine, retinoic acid, VEGF and sodium butyrate. In
addition, there is both in vivo and in vitro evidence that tPA is
acutely released from preformed stores. A rapid increase in plasma
tPA levels is observed in response to DDAVP, as well as
β-adrenergic agents, administered systemically [5].
Co-localization of VWF and tPA in the same compartment (WPB)
could account for the coordinate effect of DDAVP on the plasma
level of the two proteins. The identification of a storage
compartment for tPA, distinct from WPBs remains unexplained.
DDAVP is known to have vasodilator properties, as shown by an
increase in heart rate and a decrease in systolic and diastolic
blood pressure, as well as facial flushing. Perfusion studies have
demonstrated that vasopressin or DDAVP exert a direct vasodilatory
effect after intra-arterial administration, in a nitric oxide
(NO)-dependent manner [6]. These observations suggest a direct,
local activation of endothelial NO synthase (eNOS) in the skeletal
muscle vasculature in a V2R-dependent, cAMP-mediated manner.
DDAVP induces an increase in plasma levels of FVIII, a cofactor
of activated coagulation factor IX (FIX), responsible for the
activation of factor X (FX) of the intrinsic coagulation pathway,
leading to the formation of a fibrin clot. The effect of DDAVP on
circulating FVIII levels remains poorly understood. The plasma
level of any substance results from the balance between production
and removal. Thus, DDAVP could induce FVIII release from its
producing cells. Alternately, FVIII could be protected from
proteolytic degradation, by DDAVP-induced increase in plasma VWF,
as explained above.
The adhesion molecule P-selectin is expressed in both
endothelial cells and megakaryocytes/platelets, in WPBs and
α-granules respectively. Kanwar et al. demonstrated that DDAVP (0.1
and 1 μg/ml) induced a significant but transient increase in
P-selectin expression on human umbilical vein endothelial cells as
well as on rat and human platelets. Earlier studies have shown that
endothelial cell expression of P-selectin is important for the very
early leukocyte-endothelial cell interaction known as leukocyte
rolling, an absolute prerequisite for leukocyte adhesion and
migration [7].
As blood monocytes have been identified as a target for DDAVP,
Pereira et al. demonstrated that DDAVP enhanced the ability of
blood monocytes to bind activated platelets, mainly by increasing
the expression of P-selectin sialylated ligands on the monocyte
surface [8].
Researchers have shown that i.v. DDAVP (0.3 μg/kg) increased
2-fold the levels of plasmatic norepinephrine [9]. Concomitantly,
other authors have demonstrated that central and peripheral
administration of DDAVP increase locomotor activity in rats in
doses that alter brain dopamine neurochemistry. By using different
catecholamine manipulating agents they indicate that the central
stimulatory action of DDAVP involves granula-mediated dopamine
release and subsequent activation of dopamine receptors, and that
alpha-adrenoceptors may also be involved [10].
Secondary effects
The primary adverse reaction associated with DDAVP is hypotonic
hyponatremia. Hyponatremia has been reported in adults treated with
DDAVP for Von Willebrand’s disease and hemophilia and in children
and adults for enuresis [11]. Water intoxication is uncommon when
the drug is used with proper precautions. The strong antidiuretic
action of DDAVP has some potential problems that are negligible in
adults and older children when water intake is restricted. In
infants and small children under the age of 18 months, however,
DDAVP should be used with caution in order to prevent water
intoxication and electrolyte imbalance. Extreme caution should be
exercised when the patients receive parenteral fluid substitution
[12]. Other side effects, observed in the treatment of bleeding
disorders such as facial flushing, transient headache, increased
pulse rate and drop in systolic blood pressure are mild and
transient. They can be minimized when the dose is not exceeding 0.3
μg/kg body weights, and the infusion lasts at least 20 to 30
minutes.
Registered thrombotic episodes are few. An interesting review
analyzed the number of people treated between 1985 and 1988 in
approximately 433,000 patients and the number of published
thrombotic episodes was 10. The author concludes that the
prothrombotic risk was of 0.0001 % [13].
Biology of tumor cell invasion
To form secondary growths, cancer cells must invade the surrounding
tissue, penetrate vessels, and travel to other sites where they
arrest and resume growth. Metastasis is the major cause of
mortality in cancer patients. Of all the tumour cells that enter
into the circulation, only 0.01 % will survive to produce
secondary tumours. Metastatic capacity depends in part on
angiogenesis, a process by which the tumour induces the formation
of new blood vessels, beginning with capillary buds and progressing
to a vascular network. The new blood vessels within and around the
tumour mass provide nutrients for tumour growth and create access
to circulation for metastasis [14].
The invasion process can be classically divided into three
sequential steps: adhesion of the tumour cells to the basement
membrane and extracellular matrix (ECM), disruption of the basement
membrane by proteolytic digestion, and migration through the
modified basement membrane [14].
Adhesion of the tumour cells to the basement membrane involves
specific anchoring glycoproteins of the ECM, such as fibronectin,
collagens, and laminins, which bind to a variety of tumour cell
surface receptors. To penetrate the ECM, the invading cells must
disrupt local segments in the organized structure of the basement
membrane, a tightly regulated process involving proteases. Once the
tumour cells enter the stroma, they can easily gain access to
lymphatic and blood vessels for further dissemination.
Four major classes of proteases are important in the invasion
process: serine-, aspartyl-, cysteinyl-, and metal ion-dependent
proteases. Many subclasses of metalloproteases (MMPs) have been
described, including interstitial collagenase, type IV
collagenases, and stromelysin. Tumour invasion and metastasis
require active cell motility, not only for the endothelial cells in
the process of angiogenesis but also for the tumour cells.
Migration is initiated by pseudopodia, followed by translocation of
the entire cell. The locomotion of cells involves assembly and
disassembly of cross-linked actin filaments [15]. Once the tumour
cells gain access to a blood vessel, it is ready to circulate into
the blood and reach distant sites.
Rheologic characteristics of the metastatic cells
It has long been recognized that although a large number of cancer
cells may be released each day from primary tumours, comparatively
few metastases develop from these cells. This “metastatic
inefficiency” has been well-documented by many observations on
humans, and by several experiments involving animals. Precise
estimates of the inefficiency of circulating cancer cells in
forming tumours, is obtained from counts of pulmonary colonies in
mice 21 days after receiving tail-vein injections of 1 x
105 B16 melanoma cells [16].
Thus, even with highly aggressive transplantable tumours,
efficiencies of less than 0.1 % are common. When combined with
cancer cell loss and delay associated with intravasation, this
results in a high degree of operational metastatic inefficiency.
Kinetic studies in mice point to the massive destruction of cancer
cells in the microcirculation. As a result of interactions with
microvessel walls, it appears that some cancer cells are killed
relatively slowly, over minutes or hours by various arms of the
inflammatory and/or immunologic response, whereas others are killed
rapidly over seconds by mechanical damage [17].
Following this early evidence, Topal et al. have recently
demonstrated that aggregated colon cancer cells have a higher
metastatic efficiency in the liver compared with nonaggregated
cells. Hepatic metastases were observed in 81% of the rats after
intraportal injection of aggregates equivalent to 0.5 x
106 cancer cells. A significantly lower metastatic
efficiency (16 %) was found after the injection of 0.5 x
106 non-aggregated cancer cells [4]. Similar results
were obtained by other authors who found that in contrast with
viable single or nonaggregated cancer cells that often fail to form
metastases, cancer cell clumps or aggregates result in a high
metastatic efficiency after injection via the portal vein [18].
Aggregated cancer cells may remain in large clusters of viable
cells, and are trapped in venous or arterial branches where they
attach to the endothelial cells. Here they may be able to evade
host defence mechanisms. On the contrary, non-aggregated cancer
cells may be unable to form clusters of viable cells and are
challenged by mechanical forces and immune defences.
Metastatic tumour cells entering into the blood stream interact
with components of the haemostatic system. This interaction results
in fibrin deposition around tumour cells, determining the formation
of microthrombi that increase the efficiency of the metastatic
cascade [19]. Fibrin deposition may enhance tumour cell aggregation
and trapping in the target organ, and protect tumour cells from
destruction by host immunity [20]. In this regard, we have reported
an enhancement of lung colonization by F3II cells administering a
synthetic inhibitor of the profibrinolytic enzyme urokinase during
the first stages of metastasis formation [21].
Although the metastatic process is highly inefficient, any
release of tumour cells into circulation should be avoided. It has
been suggested that surgical manipulation can provoke release of
viable cancer cells. This fact has been confirmed by reverse
transcription-polymerase chain reaction (RT-PCR) in patients
undergoing breast cancer surgery [22]. Recently, other authors
reported the histological findings in a series of axillary lymph
node dissections taken approximately 2 weeks after breast biopsy.
They described the presence of epithelial cells in the subcapsular
sinus of draining lymph nodes that may be attributed to mechanical
transport of tumour breast epithelium secondary to the previous
surgical or needle manipulation [23].
Several experimental studies with animal models have confirmed
that intrabdominal tumour manipulation was the main factor acting
on metastatic dissemination using conventional laparotomy or
laparoscopy [24]. Port site tumour recurrence rates decreased with
increased surgical experience in a mouse adenocarcinoma model of
laparoscopic splenectomy, suggesting that a poor surgical technique
was the main cause of recurrence [25]. In the same line,
interesting results were obtained in an experimental model of
breast cancer. Syngeneic mice were inoculated into the mammary fat
pad with TA3Ha adenocarcinoma cells and the resulting tumours were
surgically excised with a curative intent. Under these conditions,
perioperative chemotherapy with doxorubicin reduced local
recurrence, axillary metastasis, and lung metastasis, and also
improved disease-free survival [26].
Desmopressin as an antitumor agent
We have examined the effects of neuropeptide hormones on our mouse
mammary carcinoma model F3II. We reported that vasopressin and its
synthetic derivative DDAVP can modulate tumour cell growth in vitro
as well as the secretion of urokinase, a profibrinolytic enzyme
involved in hematogenous metastasis. In this regard, enhancement of
pericellular fibrinolysis may prevent coating of intravascular
tumour emboli with fibrin, therefore decreasing the survival of
tumour cells in the circulation [27].
After 15 min in the presence of diluted plasma from
DDAVP-treated mice, most of the mammary tumour cells remained as a
single cell suspension. In contrast, control plasma induced a
significant tumour cell aggregation during the same time. Moreover,
a clot was formed in control tubes and tumour cell clumps were
trapped in a fibrin gel matrix. DDAVP did not reduce cell viability
of tumour cell suspensions at the doses employed. Similarly,
semiconfluent monolayers were not affected by incubation for
24-48 h in the presence of DDAVP.
We have examined the effects of desmopressin (DDAVP), on
experimental lung colonization of mammary tumour cells using the
F3II model. Coinjection of DDAVP (1-2 μg/kg body weight) at the
time of i.v. inoculation of both F3II carcinoma cells or LM3
adenocarcinoma cells significantly inhibited the formation of
experimental lung metastases. Interestingly, the inhibition of lung
metastasis was not due to direct cytotoxic effects of DDAVP on
tumour cells. Our data suggest, for the first time, that adjuvant
DDAVP therapy may impair successful implantation of circulating
mammary tumour cells.
Coinjection of DDAVP at the time of i.v. inoculation of both
F3II or LM3 cells remarkably inhibited the formation of
experimental lung metastases. The number of pulmonary nodules was
reduced about 70 % in DDAVP-treated mice. In vitro
pretreatment of tumour cells with comparable concentrations of
DDAVP followed by peptide washout did not reduce the incidence of
lung colonies, ruling out the possibility that DDAVP was mediating
its antimetastatic activity through a direct effect on tumour
cells. Inhibition of metastasis was also obtained with i.v.
administration of DDAVP 24 h after tumor cell inoculation.
Extrapulmonary tumour colonies were not found in any of the control
mice or mice treated with DDAVP.
Considering the antimetastatic effect of DDAVP in animal
studies, as well as its well-known hemostatic and fibrinolytic
properties, the compound is an excellent candidate for adjuvant
therapy both during and immediately after tumour surgery.
Therefore, we investigated the effect of DDAVP on lung and lymph
node metastatic cell colonization, using a preclinical mouse
mammary carcinoma model of subcutaneous tumour manipulation and
surgical excision [28].
We developed an experimental instrument, made of stainless
steel, for the application of controlled pressures on subcutaneous
tumours. It consists on a mobile platform that transmits pressure
though an axis to a small surface of 6 cm2. The
platform is loaded with the appropriate weight and the instrument
discharges a stable and controlled pressure (0.1-0.5
kg/cm2) on the tumour mass. Tumour-bearing mice were
anesthetized and subcutaneous tumours subjected to experimental
manipulations using pressures of 0.5 kg/cm2 during
2 min, followed (or not) by surgical excision. To examine the
antimetastatic properties of DDAVP, subcutaneous tumours were
subjected to experimental manipulations on days 14, 21, and 28 days
or on days 21 and 28, and surgically excised on day 35. DDAVP was
administered intravenously 30 min before and 24 h after
each manipulation or surgery, at a dose of 2 μg/kg. At the end of
the experiment, mice were sacrificed and autopsied.
Tumor manipulation induced massive dissemination to the axillary
nodes and increased up to 6-fold the number of metastatic lung
nodules. Perioperative treatment with DDAVP dramatically reduced
regional metastasis. The incidence of lymph node involvement in
manipulated animals was 12 % with DDAVP and 87 % without
treatment. Histopathological analysis of axillary nodes from
DDAVP-treated animals showed sinusal histiocytosis and no evidence
of cancer cells. Metastatic lung nodules were also reduced about
65 % in animals treated with DDAVP. Perioperative DDAVP
appeared to be safe at this dosage, and antitumor resistance was
obtained without overt toxic effects.
Axillary lymph nodes from most DDAVP-treated animals showed
sinusal histiocytosis. Interestingly, histiocytic reaction of the
regional lymph nodes is considered a strong indicator of antitumor
resistance in patients with breast cancer. In contrast, axillary
nodes from control mice bearing manipulated mammary tumours and
administered with the saline vehicle evidenced metastasis and
lacked sinusal histiocytosis.
Putative mechanisms of antitumor action
Further investigations will determine the precise mechanism by
which DDAVP exerts antitumor effect in mice. Nevertheless, the
haemostatic effect of DDAVP may improve the postoperative healing
process. Enhanced coagulation after tumour manipulation may
contribute to a rapid encapsulation of residual tumour tissue,
limiting intravasation of metastatic cells. Besides, DDAVP
increases intravascular fibrinolysis, helping dissolve the
protective fibrin shield of circulating tumour cells and reducing
tumour cell aggregation.
The effect of DDAVP is exerted in the early stages of
metastasis, not only by limiting the formation of tumour cell
emboli but also altering the interaction of cancer cells with
endothelium at the target organ. The possibility that the
antimetastatic properties of DDAVP are associated with a direct
cytotoxic effect was ruled out by the fact that in vitro
pretreatment of tumour cells with the peptide did not modify their
capacity to produce lung tumour colonies. Moreover, DDAVP did not
reduce the viability of either tumour cell suspensions or
semiconfluent monolayers (( figure 2 )).
However, we cannot exclude that other actions of DDAVP could
mediate the results observed. For instance, DDAVP may modify tumour
cell attachment by altering P-selectin expression on endothelial
cells [7] or platelets [29]. DDAVP may also alter haemodynamics of
blood flow or induce lysis of metastatic tumour cells through the
production of nitric oxide from the vasculature [30]. Although, we
cannot conclude that the antitumor effect is mediated via the V2
receptor, it has been described that small-cell lung cancer and
breast cancer cells express normal genes for all vasopressin
receptors and produce normal vasopressin receptor mRNAs coding for
V1a and ViB receptor proteins, as well as for both normal and
abnormal forms of the V2 receptor [31].
Conclusions and perspectives
Our data demonstrated antitumor properties of DDAVP in a mouse
mammary tumour model, using a dosage within the range routinely
administered in humans (0.3-4μg/kg). These doses have the advantage
of being well characterized from a pharmacological point of view
[32].
The present observations suggest a potential clinical
application of DDAVP during tumour resection. As the tumour is
mobilized by the surgeon, viable malignant cells are released into
the wound environment and into the circulation. This fact has been
confirmed by RT-PCR in breast cancer surgery [22]. Whatever the
mechanism of action involved, it seems that a safe drug, such as
DDAVP, may have a new clinical use: administered at the time of
surgery it may contribute to a rapid encapsulation of residual
tumor tissue, and also decrease or even prevent the metastatic
implantation of malignant cells released during the surgical
manipulation. Tissue trauma enhances the growth and spread of many
types of malignant cells. Our results suggest a potential clinical
application of DDAVP in the management of breast cancer, as well as
other aggressive solid tumours, such as melanoma, prostate, ovary,
colon, or lung cancer.
Moreover, administration of DDAVP in combination with
conventional chemotherapy may also be useful, considering the
possible mobilizing effect of chemotherapy on cancer cells.
Recruitment of tumour cells into the peripheral blood has been
reported after the first courses of primary chemotherapy in
patients with breast cancer enrolled in a prospective study [33].
In this regard, development of useful coagulation inhibitors, such
as modern low molecular weight heparins, warfarin or melagatran,
created the possibility of therapies that combine cell biological
approaches with standard chemotherapy [34]. With more and more
evidence showing that platelet activation and fibrinogen improved
the survival of circulating tumour cells the rationale of our
findings are becoming even more solid [35, 36].
The potential dual role of DDAVP in surgical oncology, reducing
blood loss through intricate profibrinolytic and hemostatic
mechanisms, and limiting tumour recurrence or metastasis, warrants
further investigation. If similar findings are obtained in humans,
pharmacologic modulation of coagulation and fibrinolysis using
DDAVP should became a priority in the management of cancer patients
undergoing surgery. Currently, a panel of linear and cyclic
vasopressin peptide analogs with improved antitumor effects is in
development in our laboratory. Amino acid substitutions in DDAVP
generate novel synthetic oligopeptides with enhanced antimetastatic
effects in animal tumour models. The antiangiogenic properties of
these compounds are also being explored.
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