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*
Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1;
Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1;
**
Laboratory for Skin Cancer Research, Laval University Medical Research Center, CHUQ, Faculty of Medicine, Laval University, 2705 Laurier Blvd., Sainte. Foy, Quebec, Canada G1V 4G2; and
Unit of Health and Environment, Hospital Research Center of Laval University, Sainte. Foy, Quebec, Canada G1V 4G2
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • rats • niacin • nitrosourea • leukopenia • anemia
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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),
thereby limiting dose and potentially decreasing treatment efficacy
(Chabner 1993
). In the longer-term, aggressive
chemotherapy treatment places the surviving cancer patient at an
increased risk for developing treatment related malignancies, as a
result of the DNA damage induced by the chemotherapy treatment. The
most frequent type of cancer observed after treatment is leukemia,
predominantly nonlymphoid in nature (Boffetta and Kaldor 1994
, Tew et al. 1996
, Tucker 1993
).
Nitrosoureas were used more extensively in the past but are still
important in the treatment of brain tumors (Chabner 1993
). Nitrosoureas spontaneously decompose to form two
reactive species, an alkylating group and a carbamoylating group, both
of which may react with DNA (Chabner 1993
), RNA and
protein. Unfortunately, nitrosoureas cause marked and often prolonged
bone marrow suppression (Chabner 1993
) and are one of
the chemotherapy drugs most strongly associated with the induction of
secondary cancers (Tucker 1993
). Ethylnitrosourea
(ENU)3
is a monofunctional ethylating agent that we have used as a simple
model of the more complex chemotherapeutic nitrosoureas. The
monofunctional nitrosoureas are potent leukemogens that model the
leukemogenic aspect of chemotherapy agents quite well, especially when
used in certain strains of rats, like Long-Evans, which respond
with primarily nonlymphoblastic leukemias (Shisa and Hiai 1985
). The alkylating capacity of nitrosoureas is primarily
responsible for their leukemogenic potential, due to the low content of
alkyltransferase protein in the bone marrow (Gerson et al. 1986
). Alkylation of DNA occurs relatively homogeneously
throughout the body due to the nonenzymatic formation of the reaction
product. This is similar to most chemotherapy drugs, which generally
cause DNA damage without cytochrome P450-mediated
bioactivation.
Cancer patients are frequently malnourished, and while this is usually
characterized as protein energy malnutrition and weight loss,
micronutrient deficiencies are also an important and understudied
problem (Inculet et al. 1987
, Shike and Brennan 1993
). Initially this may be due to the response of the body to
the disease process, which in its severe form may progress to cancer
cachexia. During treatment of the disease, chemotherapy often
exacerbates the problem by causing a loss of appetite, nausea and
vomiting (Dreizen et al. 1990
). Niacin is one of the
nutrients that appears to be deficient in many cancer (Inculet et al. 1987
) and chemotherapy patients (Dreizen et al. 1990
). Different types of chemotherapy can induce pellagra, the
clinical disease of niacin deficiency (Brown et al. 1991
, Stevens et al. 1993
). The active forms of
niacin in the cell are NAD and NADP, which exist in oxidized and
reduced forms, playing a critical role in redox metabolism. In addition
to its redox functions, NAD+ acts as the substrate for the enzyme poly(ADP-ribose) polymerase (PARP). PARP
synthesizes poly(ADP-ribose) on nuclear proteins in response to DNA
damage (Lautier et al. 1993
). PARP may be directly
involved in excision repair and regulation of a variety of stress
responses (Le Rhun et al. 1998
). However, the most
important role for the synthesis of poly(ADP-ribose) at sites of DNA
damage may be the prevention of nonhomologous recombination events
(Le Rhun et al. 1998
). Inappropriate recombination leads
to the chromosome translocations responsible for the initiation of most
leukemias (Rowley and Mitelman 1993
), including those
secondary to chemotherapy (Smith et al. 1996
). Niacin
deficiency has been shown to dramatically inhibit DNA repair in cell
culture models (Durkacz et al. 1980
, Jacobson et al. 1992
), but there is limited knowledge of its effects in the
whole animal during exposure to genotoxic agents. The poorly nourished
cancer patient, exposed to large doses of chemotherapy drugs, may
require niacin supplementation to minimize the side effects of
treatment.
We have developed an in vivo model to investigate the effect of niacin deficiency on the side effects of chemotherapy. This model demonstrates that ENU causes acute anemia and leukopenia and that niacin deficiency increases the severity of nitrosourea-induced bone marrow suppression.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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ENU and Modified Wright Giemsa Stain were purchased from Sigma Chemical (St. Louis, MO). Halothane, B.P. anesthetic was obtained from MTC Pharmaceuticals (Cambridge, Ontario, Canada). Isoton II and Zap-oglobin II were purchased from Coulter Electronics of Canada, Ltd. (Burlington, Ontario, Canada). Reticulocyte Stain (Brilliant Cresyl Blue) was purchased from ENG Scientific (Clifton, NJ).
Animals.
All animal experimentation was approved by the University of Guelph
Animal Care Committee, and animal treatment was in accordance with the
guidelines of the Canadian Council on Animal Care. Long-Evans rats
were selected for these studies due to their susceptibility to
nitrosourea-induced nonlymphoblastic leukemias (Shisa and Hiai 1985
), similar to those caused by chemotherapy in human
cancer survivors (Tucker 1993
). Weanling male
Long-Evans rats 40–50 g (Charles River Canada, St. Constant, PQ)
were individually housed in suspended wire-bottom cages and given
free access to water with a 12-h light/dark cycle. Feed intake was
determined daily. At 3 wk of age, rats were fed a niacin-deficient
(ND) diet or were pair-fed (PF), on an individual basis, identical
quantities of the same diet supplemented with exogenous niacin at 30
mg/kg diet. The diet was based on a mixture of casein (7%) and gelatin
(6%) as protein sources, to limit tryptophan availability, as
described previously (Rawling et al. 1994
). Other diet
components include cerelose (72%), celufil (5%), corn oil (5%),
mineral mix (3.5%), vitamin mix (1%), DL-methionine
(0.3%), choline bitartrate (0.2%) and nicotinic acid (30 mg/kg in
replete diets).
Chemotherapy protocol.
Using ENU, we simulated a course of chemotherapy in
nontumor-bearing rats. Rats were gavaged with 12 doses of either
ENU (30 mg/kg body weight) in water (pH 4.0) or an equivalent volume of
water (pH 4.0) alone [control (C)]. Beginning 1 wk after the
initiation of experimental diets, each rat was gavaged every second day
for 3 wk. One day after the last dose of ENU, all rats were placed on
AIN-93(Maintenance) diet (Reeves et al. 1993
) and
slightly feed-restricted, on a body weight basis, to maintain equal
intake in all rats. This model approximates the situation of a cancer
patient going through a course of chemotherapy followed by a recovery
period with a return to a higher plane of nutrition. Combinations of
diet and drug created a 2 x 2 design with PF-C, ND-C,
PF-ENU and ND-ENU treatment groups.
In Figure 4
an acute model of ENU exposure was used. Weanling
Long-Evans rats were fed ND diets or PF niacin replete diets, as
described above, for 3 wk. Rats were then treated with one larger dose
of ENU (100 mg/kg body weight) or vehicle (0 h) and killed at 3, 6, 24
and 48 h.
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At 6, 14, 22, 30, 38, 46 and 54 d postweaning, rats were anesthetized with 3% Halothane under 1.5 L/min O2 and 0.5 L/min NO, and ~100 µL of blood were taken from the orbital sinus. Peripheral blood red and white cell numbers were determined with an automated cell counter (Coulter ZM; Beckman-Coulter, Burlington, Ontario, Canada) using standard laboratory procedures. Differential counts were made from peripheral blood smears stained with Wright Giemsa stain. Reticulocytes were quantified at 30 d by mixing 10 µL fresh blood with 10 µL reticulocyte stain and incubating for 10 min at 37°C. Thin smears were counted to determine percentage positive staining and corrected using red blood cell total counts.
Statistics.
Data were analyzed by two-way ANOVA using the general linear
modeling procedure (SAS/PC; SAS Institute, Cary, NC). In the case of
significant differences in the ANOVA model, specific means (preplanned)
were compared by least square means (LSM) (
= 0.05). To
maintain clarity of the figures, significant differences are only
depicted for certain time points, as stated in the figure legends.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), including
alopecia, dermatitis, diarrhea and ataxia. Interestingly, ND-ENU
rats exhibited dramatically less severe external signs of niacin
deficiency (personal observation), in parallel with the growth effects
displayed in Figure 1
. ND-C rats gained weight less rapidly than PF-C, leading
to slightly lower body weights from 3.5 wk through to the end of the
experiment (Fig. 1)
. ND-ENU rats did not have lower body weights
than their PF-ENU counterparts, and, at 5 and 5.5 wk, had greater
body weights than ND-C rats (Fig. 1)
. Although all rats were fed
the same diet from wk 5 onward, in the same quantities, treatment
effects persisted.
|
). In ND-C rats the hematocrit was lower than with ENU
treatment alone. However, ND in combination with ENU treatment caused a
markedly lower hematocrit by the end of the treatment period. All of
these effects disappeared within 2 wk after ENU treatment and ND ended.
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). Red cell number and mean cell volume were calculated for this time
point. The changes in hematocrit were related to changes in circulating
red blood cell number and not due to changes in red cell volume (data
not shown).
Circulating reticulocytes comprised 6% of total red cells in
vehicle-dosed PF rats, which is within reference limits for rats of
this age and strain (Jain 1986
). PF-ENU rats had
reticulocyte numbers that were twice those of the PF-C rats. The
number of reticulocytes in ND-ENU rats was not higher than ND-C
rats and was significantly lower than those of PF-ENU rats. Blood
smears from PF-ENU rats revealed red blood cell fragments and
dacryocytes, or teardrop-shaped red cells. These findings indicate
damage to red cells associated with shortened lifespan or hemolytic
anemia. The ENU-induced increase in reticulocytes coupled with the
appearance of red-cell shape changes indicated that ENU treatment
alone causes hemolytic anemia with a compensatory increase in
red-cell production. In contrast, the ND rats also demonstrated
similar fragmentation and shape changes following ENU treatment
(appearance of smears, data not shown), but these rats appeared to be
unable to compensate by increasing the release of reticulocytes from
the marrow (Fig. 3
). Some data that were initially collected as part of a different
experiment support to this interpretation (Fig. 4
). When rats were fed ND diet or PF niacin replete diets for 3 wk and
then treated with one larger dose of ENU (100 mg/kg body weight), only
the ND rats showed an acute decrease in hematocrit. It is apparent from
the dramatic and rapid drop in hematocrit in ND rats that hemolytic
anemia is occurring, in the absence of internal or GI bleeding (not
observed). The PF rats can maintain hematocrit, either through release
of red blood cells from the spleen and marrow, production of new red
blood cells (higher levels of reticulocytes, Fig. 3
), lower rates of
red blood cell hemolysis or various combinations of these factors at
different times.
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), while ENU treatment caused a severe lymphopenia in both the PF and ND
groups. By the end of the treatment period, ND in combination with
ENU caused circulating lymphocytes to drop to numbers 40% lower than
those seen in the PF-ENU group, but this difference was not
significant when tested by LSM (P = 0.17). The
lack of significance may have been due to the variance of the control
groups, which had much greater numbers of lymphocytes. This is
supported by the fact that a direct comparison by t test
showed that the ND-ENU group has significantly fewer lymphocytes
than the PF-ENU group.
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). When changed to the postchemotherapy diet, with a cessation of feed
restriction, there was a further increase in granulocyte numbers, which
gradually returned to normal as the refeeding period progressed. Two
weeks of ENU treatment caused significant neutropenia in
niacin-replete rats (PF-ENU), but this was not significant at the
end of the ENU treatment period. In contrast, although ND-ENU rats
had higher absolute numbers of neutrophils than PF-ENU rats, the
degree of ENU-induced neutropenia (% change) was much greater in
ND rats, and the ENU effect was significant in ND rats after 2 and 3 wk
of ENU treatment.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Chemotherapy patients are often granulocytopenic such
that bacterial and fungal infections are a major cause of morbidity and
mortality (Gabrilove and Golde 1993
). Akylating agents
have been shown to suppress lymphocyte number and function, leading to
an increased frequency of viral, fungal and protozoal infections
(Pizzo et al. 1993
,Tew et al. 1996
).
However, because alkylating agents have tumor-killing success, it
would be beneficial to establish means to protect the marrow, not only
from short-term toxicity, but also from the longer-term effects
of alkylating agents.
It has been reported that niacin deficiency causes anemia in
pellagrins (Spivak and Jackson 1977
, Gillman and Gillman 1951
), as we observed in ND rats. Observation of the
peripheral blood smears, absence of hemorrhage and an elevated
reticulocyte count in ENU-treated PF rats suggest that
niacin-replete rats are able to compensate for red cell destruction
caused by ENU. The absence of an increase in reticulocyte number in the
ND-ENU rats shows that ENU impairs the regenerative capacity of ND
bone marrow, leading to the more severe anemia of the ND-ENU group.
Our data show that niacin deficiency enhances the susceptibility of
lymphocyte precursors to alkylating agents, an effect that could place
chemotherapy patients at a greater risk of infection. The changes in
neutrophil populations, in the absence of chemotherapy and without any
apparent infectious disease in the rats, suggest that niacin deficiency
increases neutrophil production by the bone marrow. Interestingly,
blood data from early pellagra studies suggest that neutrophilia also
occurs in humans who are deficient in niacin (Gillman and Gillman 1951
). The large increase in neutrophil numbers in
niacin deficiency and their decimation by ENU treatment suggests that
this population may be susceptible to ENU-induced leukemogenesis.
Signals causing rapid division of neutrophilic precursors during
exposure to ENU could limit effective DNA repair, leading to the
accumulation of mutations and giving rise to the acute nonlymphoblastic
leukemias that often occur as secondary malignancies.
Our observation that ND-ENU rats gained more weight and
exhibited fewer signs of niacin deficiency than ND-C rats shows
that ENU has complex effects in the whole animal. The decrease in
severity of the classical signs of niacin deficiency in the ND-ENU
rats is difficult to explain, but it is possible that the decimation of
neutrophils by ENU (Fig. 6)
helps to minimize the inflammatory
responses caused by niacin deficiency in the skin and gastrointestinal
tract. The metabolic cost of neutrophilia and the potential side
effects of excessive inflammation may also account for the increase in
growth rate for the ND-ENU compared to the ND-C rats.
It is possible that the effect of niacin deficiency on
ENU-induced bone marrow suppression that we have reported is due to
alterations in drug metabolism. Previous data from our laboratory
suggest that it is unlikely that changes in
P450-mediated metabolism are involved in this
effect. Bone marrow itself has very low P450
content (Bernauer et al. 1999
), and decreased hepatic
clearance of ENU via P450-mediated metabolism is
unlikely considering that niacin deficiency in this dietary model has
no effect on the hepatic bioactivation of diethylnitrosamine
(Rawling et al. 1995
). The spontaneous decomposition of
ENU to reactive species may be rapid enough to prevent a significant
influence of metabolic clearance of the parent compound. We are
currently conducting experiments to measure the level of DNA damage in
ND vs. PF rats, so that we can answer this question directly.
By what mechanism does niacin deficiency increase the sensitivity
of the bone marrow to alkylating agents? One compelling explanation
involves a decrease in PARP formation due to low levels of the
substrate, NAD+. PARP synthesis by PARP is
induced by DNA damage and thought to be involved in DNA repair,
prevention of recombination, regulation of p53 expression and control
of apoptosis (Le Rhun et al. 1998
). The complexity of
this field is increasing rapidly with the discovery of four additional
enzymes that synthesize PARP and appear to have roles in telomere
stability and length (Smith et al. 1998
), ribonuclear
protein function (Kickhoefer et al. 1999
) and cellular
responses to DNA damage (Ame et al. 1999
). Future work
in this area will require the characterization of
NAD+ and PARP metabolism in the bone marrow in
response to niacin deficiency and DNA damage.
It is obvious that this manuscript describes a simplified model,
lacking the complexities of existing neoplastic disease and the effects
of multiple chemotherapy drugs (Inculet et al. 1987
),
but the following observations can be made. Niacin repletion prior to
ENU treatment could fully reverse ENU effects on hematocrit and
actually allow an increase in this variable. This can be traced to the
effect of niacin status on ENU-induced reticulocyte formation,
which is greatly enhanced in niacin-replete group. The depletion of
lymphocytes is more severe in the ND-ENU compared to the PF-ENU
rats. Taken together, the data show that niacin deficiency
increases the sensitivity to ENU of the bone marrow precursors for red
blood cells, neutrophils and lymphocytes, leading to changes which
could have a negative impact on the health of chemotherapy patients.
Further work will be required to establish long-term responses and
the implications of concurrent neoplastic conditions.
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FOOTNOTES |
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3 Abbreviations used: C, vehicle control; ENU,
ethylnitrosourea; LSM, least square means; ND, niacin-deficient; PARP,
poly(ADP-ribose) polymerase; PF, pair-fed.
Manuscript received September 20, 1999. Initial review completed October 28, 1999. Revision accepted December 16, 1999.
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