Velafermin improves gastrointestinal mucositis following irinotecan treatment in tumor-bearing DA rats.

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e1 Cancer Biology & Therapy 2007; Vol. 6 Issue 4
Research Paper
Velafermin Improves Gastrointestinal Mucositis Following Irinotecan
Treatment in Tumor-Bearing DA Rats
Rachel J. Gibson1,2,*
Andrea M. Stringer1,2
Joanne M. Bowen2
Richard M. Logan3
Ann S.J. Yeoh1,2
Jaimi Burns1,2
Enrique Alvarez4
Dorothy M.K. Keefe1,2
1Department of Medical Oncology; Royal Adelaide Hospital; 2Division of Medicine;
The University of Adelaide; Adelaide, South Australia
3Oral Pathology, School of Dentistry, The University of Adelaide; Adelaide, South
Australia
4CuraGen Corporation, Branford, Conneticut USA
*Correspondence to: Rachel J. Gibson; Department of Medical
Oncology; The Royal Adelaide Hospital; North Terrace, Adelaide 5000
South Australia, Australia; Tel.: +61.8.8222.3261; Fax: +61.8.8222.3217;
Email: rachel.gibson@adelaide.edu.au
Original manuscript submitted: 09/07/06
Manuscript accepted: 01/13/07
This manuscript has been published online, prior to printing for Cancer Biology &
Therapy, Volume 6, Issue 4. Definitive page numbers have not been assigned. The
current citation is: Cancer Biol Ther 2007; 6(4):
http://www.landesbioscience.com/journals/cc/abstract.php?id=3848
Once the issue is complete and page numbers have been assigned, the citation
will change accordingly.
KEY woRDS
velafermin, irinotecan, gastrointestinal muco‑
sitis, diarrhoea
AcKnowLEDGEMEntS
The authors gratefully acknowledge CuraGen
for the supply of the velafermin and Pfizer
for the supply of irinotecan. In addition,
the authors acknowledge Dr. John Finnie
for expert histopathologic advice. Dr. R.J.
Gibson was supported by a Cancer Council
South Australia Research Fellowship, Dr. J.M
.Bowen was supported by a Dawes Research
Scholarship and Ms. A. Yeoh was supported
by a Florey Research Scholarship for the dura‑
tion of this project. Research was supported
by a CuraGen Unrestricted Educational Grant
(to DMKK).
ABStRAct
Mucositis is a common, costly and unpleasant side effect of cancer chemotherapy and
radiotherapy. Velafermin (FGF‑20) has shown the potential to reduce these side effects.
Irinotecan is a chemotherapeutic agent which is commonly used in solid tumors, and
causes GI mucositis manifested by severe diarrhoea. Therefore the primary aim of this
study was to investigate whether velafermin reduces the GI mucositis induced by irino‑
tecan. The secondary aim was to test varying schedules of administration of velafermin.
Groups of tumor‑bearing DA rats (6 per group) were treated with varying doses (4,
8 or 16 mg/kg) of velafermin intraperitoneally either prior to, prior to and during, or
after chemotherapy treatment. Rats received a single dose of 200 mg/kg irinotecan
intraperitoneally. Rats were monitored closely for the incidence and severity of diarrhoea
and mortality before being killed 192 h following treatment. Mortality, diarrhoea and
histopathology were assessed throughout the gastrointestinal tract. Severe or moderate
diarrhoea occurred in approximately 40% of rats treated with irinotecan alone. This
was associated with a 50% mortality rate 96 h following chemotherapy. Velafermin
administered at 16 mg/kg prior to irinotecan improved gastrointestinal mucositis as
measured by reduced diarrhoea and mortality following irinotecan chemotherapy in the
DA rat. Rats that received velafermin prior to, or prior to and during irinotecan treatment
did develop severe or moderate diarrhoea, however it occurred later, in fewer rats and
was not associated with mortality. Other dosing regimens were not as effective. This has
important implications for the use of velafermin in GI mucositis in humans, and should
be further studied.
IntRoDuctIon
Mucositis is a major oncological problem caused by the cytotoxic effects of cancer
chemotherapy and radiotherapy. It affects the entire gastrointestinal tract, (GIT) from
the mouth to the anus and causes significant pain and ulceration in the oral cavity and
oropharynx. In addition, symptoms such as abdominal bloating, vomiting and diarrhoea
result from mucositis occurring in the small and large intestines.1‑3 These unpleasant
symptoms cause patients considerable distress and can lead to reduction in doses of chem‑
otherapy, which reduces the chances of remission.1,4,5 Management of mucositis has, until
very recently, been largely limited to pain relief, maintenance of good oral hygiene and the
use of fluids and loperamide (a non‑analgesic opioid) for diarrhoea. Recently, Palifermin
(Amgen, Keratinocyte Growth Factor 1, Fibroblast Growth Factor 7) has been licensed
for use in the prevention of oral mucositis (OM) in the bone marrow transplant setting.6
Animal work with Palifermin has shown promise for its use in gastrointestinal mucositis
(GIM),7 but confirmatory human trials have not yet been performed. In addition, safety
concerns such as the potential for its effects on epithelial tumor growth have still to be
satisfactorily addressed. One of the problems is that the mechanism of development of
mucositis is still not fully understood, making it hard to target treatment. However, since
the GIT has the same embryological route of development (being formed from primi‑
tive endoderm with ectodermal inpouching at the extremes), it is highly likely that the
biological events that result in mucositis will be the same throughout the entire tract1,4,8,9
with regional differences being due to specialised local differentiation necessary for local
functional requirements.
Irinotecan hydrochloride is a common and effective chemotherapeutic drug used in
the treatment of gastrointestinal cancers. Administration of this drug however, causes two
forms of diarrhoea, an early cholinergic diarrhoea and a severe delayed diarrhoea, both of
which are distressing to patients and can cause disruptions in treatment.10,11 Currently
[Cancer Biology & Therapy 6:4, e1‑e7, EPUB Ahead of Print: http://www.landesbioscience.com/journals/cbt/abstract.php?id=3848; April 2007]; ©2007 Landes Bioscience

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Velafermin and Gastrointestinal Mucositis
there is no known preventative agent for gastrointestinal mucositis.
Development of an appropriate agent could lead to improvements in
the care of oncology patients and reduce the distressing side effects
of therapy.
Velafermin (FGF‑20) is a member of the fibroblast growth factor
family.12‑14 Members of this family have been previously implicated
in normal growth and development of the GIT,12‑14 with receptors for
FGFs found within the intestinal epithelium.15,16 Previous research
has demonstrated that certain FGF family members are involved in
the repair and proliferation of the intestinal epithelium; this being
highly suggestive of a role in repair following injury.15‑19 Other
members of the FGF family (FGF‑7, now known as Palifermin) have
previously been investigated as potential anti‑mucotoxics throughout
the GIT and have shown promising results.7,20‑22 Velafermin has
previously demonstrated activity in models of ulcerative colitis12
and oral mucosal damage following cytotoxic insult.14 Recent results
from a Phase I clinical trial examining velafermin, have indicated that
the drug is well tolerated following intravenous administration.23
Phase II clinical trials are now underway to investigate if velafermin
is effective in preventing oral mucositis. However, its effects in the
remainder of the GIT need further investigation. Therefore the aims
of in this study were to establish whether treatment with velafermin
can alter the time‑course, incidence and/or duration of gastrointes‑
tinal mucositis after a 1‑day induction of mucositis with irinotecan.
MAtERIALS AnD MEthoDS
Ethics. The studies described here were approved by the Animal
Ethics Committees of The Institute of Medical and Veterinary
Sciences and of The University of Adelaide and complied with the
National Health and Medical Research Council (Australia) Code of
Practice for Animal Care in Research and Training (2004). Due to
the potentially severe nature of the diarrhoea that can be induced by
irinotecan, animals were monitored four times daily and if any animal
showed certain criteria (as defined by the Animal Ethics Committee)
they were euthanised. These criteria included a dull ruffled coat with
accompanying dull and sunken eyes, cool to touch with no sponta‑
neous movement and a hunched appearance. Mortality in this study
therefore was defined as an animal that had to be euthanised or died
prior to its scheduled time point.
Passage of tumor. The mammary adenocarcinoma used in this
study has been used by our group for a number of years and its
passage has been described elsewhere.3,24,25 This tumor is specific to
the dark agouti (DA) rat. Mammary adenocarcinoma tumors were
diced, homogenised and then filtered through sterile gauze. The
resulting tumor cell suspension was spun three times at 1100 rpm for
three min each time, with the resultant pellet resuspended in fresh
PBS prior to the next spin. A viable cell count was conducted using
0.4% w/v trypan blue.
Experimental design. All experiments described were conducted in
female DA rats, weighing between 170 g and 200 g. All rats received
breast cancer inoculum of 4.0x106 cells in 0.15 ml phosphate buffer
(PBS) s.c. into each flank as described above. Tumors were allowed to
grow for seven days prior to rats receiving irinotecan.
Statistics. The studies described below are initial exploratory dose
finding and scheduling studies and as such were not powered to
undergo statistical analysis. They are purely descriptive studies.
Study 1. Rats were randomly assigned to various treatment
or placebo groups with 6 animals per group prior to the study
commencement (Table 1). Briefly, all rats received 0.01 mg/kg
subcutaneous atropine (to reduce any cholinergic reaction to irino‑
tecan) immediately (within 2 mins) prior to administration of a
single intraperitoneal dose of 200 mg/kg of irinotecan (previously
shown to cause reproducible gastrointestinal mucositis), or placebo.
Irinotecan (kindly supplied by Pfizer) was administered in a sorbitol/
lactic acid buffer (45 mg/ml sorbitol/0.9 mg/ml lactic acid pH 3.4),
required for activation of the drug, on day designated 0. Rats then
received varying doses and schedules of velafermin intraperitoneally
over the next 7 days (Table 1). During this period the following
endpoints were assessed four times per 24 h period: mortality, body
weights, diarrhoea and general clinical condition.3,7 Diarrhoea was
scored using standard methodology described elsewhere. At 192 h (8
d) after the irinotecan injection all rats were killed and various organs
were dissected for further examination.
Study 2. The basic experimental design was similar, with animals
prepared under identical conditions to Study 1. Rats were randomly
assigned to various treatment or placebo groups prior to study
commencement. Briefly all rats received 0.01 mg/kg subcuta‑
neous atropine (to reduce any cholinergic reaction to irinotecan)
immediately (within 2 minutes) prior to administration of a single
intraperitoneal dose of 200 mg/kg of irinotecan or placebo. Rats
received 16 mg/kg/day of velafermin intraperitoneally, over varying
treatment schedules, either prior to, during, or after chemotherapy
(Table 2). During the entire experimental period the following
Table 1 Experimental design study 1
Group Induction treatment treatment Schedule
1 None None None
2 0.01 mg/kg Atropine + 200 mg/kg Irinotecan None None
3 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 4 mg/kg/day Velafermin Day 1
4 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 4 mg/kg/day Velafermin Days 1–2
5 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 4 mg/kg/day Velafermin Days 1–7
6 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 8 mg/kg/day Velafermin Day 1
7 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 8 mg/kg/day Velafermin Days 1–2
8 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 8 mg/kg/day Velafermin Days 1–7
9 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Day 1
10 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Days 1–2
11 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Days 1–7
12 None 8 mg/kgday Velafermin Days 1–7

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endpoints were assessed four times per 24 h period: mortality,
bodyweight, diarrhoea and general clinical condition. Diarrhoea was
scored using standard methodology described elsewhere.3,7 At 192
h (8 d) after the irinotecan injection, all rats were killed via cardiac
puncture and cervical dislocation. As in study 1, various organs were
taken for histological examination.
Clinical observations and diarrhoea assessment. All animals were
assessed four times daily following the administration of irinotecan.
Clinical record sheets were maintained and records kept for presence
of dull/ruffled coats; change in temperament (including squealing
when handled and stress marks on paws and face), diarrhoea, reluc‑
tance to move and weight loss. Diarrhoea was recorded according to
established gradings.3 Briefly there were 4 grades: 0: no diarrhoea;
1: mild diarrhoea (staining of anus); 2: moderate diarrhoea (staining
over the top of the legs and lower abdomen); 3: severe diarrhoea
(staining over the legs and higher abdomen, often associated with
continual oozing). All diarrhoea assessments were conducted in a
blinded fashion by three investigators (RJG, AMS, JMB).
Organ weights. The gastrointestinal tract (from the oesophagus
to the rectum) was dissected out. The intestines were separated from
the oesophagus and stomach and were flushed with chilled isotonic
saline. The wet weights of oesophagus, stomach, small intestine and
colon were recorded. Small (1 cm in length) samples of the small
intestine (taken at 25% of the length of the small intestine from
the pylorus) and colon (taken at mid colon position) were collected
and placed into 10% formalin for histological examination. In addi‑
tion small samples of oesophagus and stomach were fixed in 10%
formalin. The tumors were removed and weighed. Small (approxi‑
mately 1 cm) cross‑sections of non‑necrotic tumor were dissected and
placed into 10% formalin for histological examination. In addition,
weights of the liver and spleen were recorded. Small samples were
fixed in 10% formalin for examination.
Histopathological examination. Samples of jejunum, colon, liver
and spleen were taken, weighed and fixed in 10% neutral buffered
formalin for routine histological examination as previously described.3
Expert histopathological examination of representative sections from
each group was performed by specialist veterinary pathologist, Dr.
John Finnie, from the Institute of Medical and Veterinary Science,
(Adelaide, Australia). This examination was performed in a blinded
fashion.
RESuLtS
Response to treatment. Study 1. Mortality. Velafermin treatment
resulted in significantly reduced mortality when given on day 1 at
the doses (4 and 8 mg/kg), with no rats dying as a result of treatment
(Fig. 1A). Multiple doses of velafermin at the 8 mg/kg dose resulted
in worse mortality when compared to irinotecan alone (Figs. 1B and
1C). All other multiple doses resulted in similar or higher mortality
rates compared with irinotecan alone (Fig. 1). Hence, single doses of
velafermin with 4 or 8 mg/kg, given on day 1, improved mortality
after irinotecan treatment.
Diarrhoea. Rats receiving irinotecan alone developed both early
and late diarrhoea following chemotherapy. The early diarrhoea
(defined as that which occurred in the first 24 h after treatment) was
mild in nature, and was generally transient. By 24 h after treatment,
approximately 32% of rats had mild diarrhoea and 18% of rats had
moderate diarrhoea. The peak incidence of diarrhoea was 72 h after
treatment when approximately 22% of rats developed severe diar‑
rhoea and 60% of rats developed moderate diarrhoea. After this time
point, diarrhoea improved. These results, with the peak incidence of
diarrhoea at 72 h after chemotherapy treatment, are consistent with
our previous studies.3,7,26
Rats receiving 4 mg/kg velafermin in all dosing schedules devel‑
oped severe diarrhoea which began earlier and lasted longer than rats
receiving irinotecan alone (Fig. 2). A similar pattern was observed
in rats receiving 8 mg/kg velafermin over all treatment schedules,
with severe diarrhoea beginning earlier and lasting longer than rats
receiving irinotecan alone. 100% of rats that received 2 x 8 mg/kg
velafermin developed severe diarrhoea 72 h after irinotecan treat‑
ment. Rats receiving 16 mg/kg velafermin had severe diarrhoea that
began earlier and lasted longer than rats receiving irinotecan alone
(Fig. 2). However, of the three treatment doses, 16 mg/kg velafermin
resulted in the earliest resolution of diarrhoea. Rats that received vela‑
fermin only (7 x 8 mg/kg velafermin) without irinotecan, developed
no diarrhoea at any time points (Fig. 2).
Bodyweights. All rats that received irinotecan lost weight.
Velafermin did not cause excessive weight loss, nor did it appear to
maintain weight in rats following treatment with irinotecan. Rats
receiving no irinotecan or velafermin alone continued to gain weight
for the duration of the study.
Gross Pathology. Autopsies were performed on all rats that died
prematurely. Rats had evidence of peritonitis with perforations
observed in the duodenum, fatty lysis and excess fluid in the peritoneal
Table 2 Experimental design study 2
Group Induction treatment treatment Schedule
1 None None None
2 0.01 mg/kg Atropine + 200 mg/kg Irinotecan None None
3 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Day ‑1
4 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Days ‑2 and ‑1
5 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Days ‑2 to 0
6 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Day ‑2 to +1
7 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Day ‑2 to +2
8 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Day 0
9 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Day ‑2 to +7
10 0.01 mg/kg Atropine + 200 mg/kg Irinotecan 16 mg/kg/day Velafermin Day 0 to +7

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Velafermin and Gastrointestinal Mucositis
cavity and intestinal adhesions to the walls of the
peritoneal cavity. These results were consistent
with previously published results.3,7,26
Therefore subsequent studies were necessary
as previous pre‑clinical studies using velafermin
indicate the importance of correct administra‑
tion schedules.14
Response to treatment. Study 2. Mortality.
Overall, twenty percent of the rats in this study
died prematurely. Rats receiving irinotecan alone
had a 50% mortality 96 h after chemotherapy (Fig.
3A). Rats receiving irinotecan and 16mg/kg vela‑
fermin on days ‑2 to +2 had approximately 18%
mortality rate 168 h after irinotecan treatment
(Fig. 3B). Rats receiving irinotecan and 16 mg/
kg velafermin from day 0 to day 7 inclusive had
approximately 16% mortality rate 72 h after
chemotherapy and an 80% mortality rate 96 h
after chemotherapy treatment (Fig. 3C). Rats
treated with irinotecan and velafermin on day
0 had approximately 16% mortality rate at 96
h, a 20% mortality at 120 h and 25% mortality
at 192 h after treatment (Fig. 3C). One rat
died 120 h after treatment in the velafermin
from days ‑2 through to +7 group (Data not
shown).
Diarrhoea. Rats that received irinotecan only,
had diarrhoea which was initially transient
and appeared to improve over the first couple
of days, before approximately 40% of rats
developed severe and moderate diarrhoea at
72 h respectively. This is consistent with our
previous studies.3,7,26 The remaining 20% of
rats did not have any diarrhoea. The diarrhoea
improved from this time point on and from
120 h there was no diarrhoea recorded (Fig.
4). Rats receiving 16 mg/kg velafermin prior
to, but not after, chemotherapy treatment had
a different pattern of diarrhoea from those
receiving chemotherapy only. Initially the diar‑
rhoea was transient and was mainly mild with
approximately 20% of rats developing moderate
diarrhoea. Severe diarrhoea did develop in each
of these groups, however it occurred later, in
fewer rats, and generally lasted for a shorter
time than in rats receiving irinotecan only (data not shown). In rats
receiving velafermin treatment for the two days prior to, and the two
days prior to and on the day of chemotherapy, severe diarrhoea was
observed 96 h after treatment. This had generally resolved by 120 h
(Fig. 4).
For all other treatment schedules of velafermin, the diarrhoea
observed was worse than seen in control animals treated with irino‑
tecan alone.
Body weights. Rats receiving no chemotherapy continued to gain
weight for the duration of the study. Rats in all other treatment
groups lost weight over the first 96 h following irinotecan treatment,
with rats receiving velafermin from day 0 through to day 7 losing the
most weight. After this time point rats steadily gained weight and
most had returned to their pre chemotherapy treatment weight by
the end of the study (Data not shown).
Gross Pathology. Autopsies were performed on all rats that died
prematurely. Rats had evidence of peritonitis with perforations
observed in the duodenum, fatty lysis and excess fluid in the peri‑
toneal cavity and intestinal adhesions to the walls of the peritoneal
cavity. These results are consistent with previously published results.
One rat which died 168 h after chemotherapy administration had no
obvious cause of death. This rat had received 200 mg/kg irinotecan
and 16 mg/kg velafermin from days ‑2 through to +7. The autopsy
appeared normal, with no evidence of inflammation, peritonitis,
excess fluid or adhesions.
Histopathology. Representative slides of jejunum, colon, liver and
spleen were sent to specialist veterinary pathologist Dr. John Finnie.
These were assessed in a blinded fashion. As expected control rats
showed no significant histological changes in the jejunum or colon,
however in the liver an occasional apoptotic body was observed.
Figure 1. Graph showing mortality over time from Study 1 in rats pretreated with single, two or
seven doses of 4 mg/kg, 8 mg/kg or 16 mg/kg of velafermin. Rats that received 4 mg/kg of
velafermin showed no mortality at any time point investigated. Rats that received multiple doses of
velafermin at either 8 mg/kg showed an increase in mortality rats when compared to controls or
irinotecan alone. Other multiple doses of velafermin resulted in a similar mortality rate to irinotecan
alone.

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Rats receiving chemotherapy only, showed marked hyperplasia
with occasional villous clubbing in the jejunum, however there were
no significant histological findings in the colon. Rats receiving 16
mg/kg velafermin prior to receiving chemotherapy (day ‑2 to 0)
showed marked hyperplasia with clubbing and fusion of villi in the
jejunum. In the colon, there was evidence of crypt dilation, lined
with attenuated epithelium, cellular debris and excess mucin in the
lumina. Rats receiving velafermin for the two days prior to and the
two days following chemotherapy showed jejunal tissue that was
hyperplastic with some clubbing and fusion of the villus. In the
colon there were a few crypts that were dilated, lined with attenuated
epithelium, with minimal necrotic debris in the lumina. Rats that
received velafermin from day 0 through to day 7 showed no signifi‑
cant histological changes in the jejunum or colon, but in the liver a
diffuse hydropic change to hepatocyes was recorded.
DIScuSSIon
Gastrointestinal mucositis is a major problem in oncology, caused
by the cytotoxic effects of cancer chemotherapy and radiotherapy.
To date, the mechanisms are not fully defined. Recent literature has
provided clear evidence that the entire GIT follows a similar pattern
of development of mucositis.1,4,7‑9 The GIT has the same embryo‑
logical route of development being formed from primitive endoderm
with ectodermal inpouching at the extremes, with differences seen
being due to cellular differentiation at various sites in order to
conduct specialised functions. Consequently an hypothesis has been
proposed which characterises mucositis as a consequence of a cascade
of biological events;8,27–29 that are not independent of each other,
with significant overlap.
Irinotecan is a highly effective chemotherapeutic agent in certain
tumors, however its use is limited by the severity of the diarrhoea
that it causes, making an otherwise effective drug very difficult to
use clinically. Whilst oral loperamide works to reduce diarrhoea in
many patients,30 a significant number of patients develop grade 4
diarrhoea ultimately leading to cessation of treatment.10,11,31 In some
patients this diarrhoea may be life threatening. Previous research
has shown that velafermin is an effective antimucotoxic in animal
models of oral mucositis,14 and it therefore may also be effective in
gastrointestinal mucositis. An anti‑mucotoxic that would reduce the
diarrhoea caused by irinotecan would improve the clinical options,
particularly in colon cancer, but also in other tumors. The aims of the
Figure 2. Incidence of diarrhoea over time in rats pretreated with single, two or seven doses of 4 mg/kg, 8 mg/kg or 16 mg/kg of velafermin. Rats that
received 4 mg/kg or 8 mg/kg of velafermin developed severe diarrhoea which was worse than rats receiving irinotecan alone. 16 mg/kg of velafermin
also resulted in severe diarrhoea, however it resolved quickly.