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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2471-2476
Nutritional Folate Status Influences the Efficacy and Toxicity of
Chemotherapy in Rats
By
Richard F. Branda,
Elizabeth Nigels,
Amy R. Lafayette, and
Miles Hacker
From the Departments of Medicine and Pharmacology and the Vermont
Cancer Center, University of Vermont, Burlington, VT.
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ABSTRACT |
The effect of folate status on the efficacy and toxicity of
chemotherapy was investigated in weanling Fischer 344 rats maintained on diets of varying folate content or supplemented with daily injections of folic acid, 50 mg/kg, for 6 to 7 weeks. MADB106 rat
mammary tumor growth rate was the same in folate replete and supplemented rats, but retarded in the low folate groups. The tumor
growth inhibitions in low folate, replete and high folate rats treated
with cyclophosphamide were: 53%, 98%, and 97% (P = .048);
with 5-fluorouracil (5-FU): 46%, 49%, and 66%; and with doxorubicin:
25%, 55%, and 61%. Significant differences in survival were observed
for cyclophosphamide (P = .0084) and 5-FU (P = .025) related to dietary folate content. Thus, folate deficiency
impedes tumor growth rate, but supplementation does not accelerate it in folate replete animals. Correction of folate deficiency
approximately doubles the efficacy of cyclophosphamide in rats with
much less host toxicity. Folate repletion improves survival in
5-FU-treated animals. These studies indicate that nutritional folate
status has an important influence on the efficacy and toxicity of some commonly used cancer chemotherapeutic drugs.
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INTRODUCTION |
FOLIC ACID DEFICIENCY has been observed
in patients with cancer due to the combination of inadequate dietary
folacin content, poor dietary intake, and the increased metabolic needs
imposed by malignancy.1 For example, Magnus2
reported that in a series of patients with metastatic cancer, 85% had
abnormally low serum folate levels and 16% had low red
blood cell folate levels. Clamon et al,3 in a
study of lung cancer patients, noted that 36.7% of patients with
limited stage disease, 38.5% of patients with hepatic metastases, and
47.1% of patients who had lost more than 9% of body weight had
reduced serum folate levels. However, clinicians are uncertain about
the management of folic acid deficiency in patients with cancer. In
1948, Farber et al4 described acceleration of the leukemic
processes by folic acid conjugates to a degree not encountered in other
children with acute leukemia, and Heinle and Welch5
reported that administration of folic acid to three patients with
chronic myeloid leukemia was attended by rapid hematologic and clinical
relapse in each case. Subsequent studies in rodents confirmed that
dietary restriction of folic acid inhibited the growth of tumors. Rosen
and Nichol6 reported that when rats were placed on a
folate-deficient diet 2 weeks before transplantation of Walker
carcinosarcoma 256, tumor growth was inhibited by 95% on the 28th day
after transplantation. The tumor remained viable and resumed rapid
growth when folate was added to the diet.6 Potter and
Briggs7 similarly found that dietary folate deficiency in
mice retarded the growth of ascites tumor cells of lymphocytic
neoplasms. An attempt to extend these animal studies to humans by
placing seven patients with advanced malignancies on a folate-deficient
diet for periods ranging from 25 to 140 days was unsuccessful, as no
antitumor effect was noted.8 Nevertheless, clinicians
generally have been reluctant to administer folic acid to deficient
cancer patients on the chance that the vitamin might accelerate the
growth of the malignancy.
Recently, folic acid deficiency during early pregnancy has been
associated with birth defects. Consequently the Food and Drug Administration has proposed that the diet of all Americans be fortified
with 140 µg of folic acid per 100 g of cereal-grain product.9 The effect of this dietary supplementation with
folic acid on cancer patients is unclear, but of concern. The influence of subnormal or supranormal levels of folic acid on the efficacy and
toxicity of chemotherapy has received relatively little attention, despite the fact that substantial numbers of patients with cancer are
likely to have a nutritional abnormality of folate metabolism or are
taking supplemental vitamins, often in megadoses.10
Therefore, the studies described herein were designed to investigate
the interaction of nutritional folate status and response to
chemotherapy.
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MATERIALS AND METHODS |
Animals.
Weanling female Fischer 344 rats (weighing approximately 60 g) were
obtained from Charles River Canada (St-Constant, Quebec). The rats were
maintained in groups of three or four for 10 days and fed standard rat
chow (Teklad 7012; Harlan Teklad, Madison, WI). Then rats were housed
individually in stainless steel wire-bottomed cages. Their diets were
either folate replete (AIN-93G Purified Rodent Diet with Vitamin Free
Casein containing 2 mg folic acid/kg of diet), low folate (AIN-93G with
vitamin mix lacking folic acid), or very low folate (AIN-93G with
vitamin mix lacking folic acid and with 1% succinyl sulfathiazole),
all obtained from Dyets, Inc (Bethlehem, PA). At the completion of the
study, the rats were anesthetized with pentobarbital sodium (60 mg/kg
intraperitoneally [IP]) and exsanguinated by cardiac puncture.
Samples were collected for subsequent folate analyses using previously
described methods.11,12 Approximately two
thirds of blood removed was allowed to clot at room
temperature, the serum was then separated by centrifugation and frozen
in 100 µL aliquots at  70°C. The remaining one
third was added into a tube containing EDTA to prevent
clotting, diluted 1:9 with distilled water containing 1% ascorbic
acid, and frozen at 70°C in 1-mL aliquots. The liver was
weighed and 1 g homogenized in 3 vol 140 mmol KCl/L. The homogenate was
then diluted 1:9 with 50 mmol potassium phosphate/L, pH 4.8, containing
1% ascorbic acid, and incubated for 24 hours at 37°C to allow
endogenous conjugase to convert folate polyglutamates to
monoglutamates. Afterwards, the homogenates were autoclaved, cooled on
ice, and centrifuged at 2,000g for 10 minutes. The supernatants
were frozen in three 1-mL aliqouts at 70°C. All animal
protocols and care were approved by the Institutional Animal Care and
Use Committee of the University of Vermont.
Folate assay.
The tissue folate levels were measured on the aformentioned frozen
samples by an assay that uses a bacteria that grows only in the
presence of folate.13,14 The growth turbidity of
Lactobacillus casei (L casei), which grows in
proportion to the amount of folic acid present, was measured in a
96-well plate on a microplate reader.13 A standard curve
ranging from 0.0625 to 2 ng/well was made using folinic acid, as it is
more stable than folic acid.13 Tissue samples were diluted
as needed to fit within the parameters of the standard curve. The
standard curve, as well as the samples, were diluted in Sorenson's
phosphate buffer with 1 mg/mL of ascorbic acid, pH 6.3.13
Double strength maintenance media (DIFCO, Detroit, MI)
with .5 mg/mL ascorbic acid was added to each plate at 150 µL/well.
The ascorbic acid was added to double strength maintenance medium and
Sorenson's buffer and filter sterilized just before plating. L
casei was diluted 7:1 with Sorenson's phosphate buffer and added
at a concentration of 80 µL/well. The addition of 80 µL/well of
either sample, folate for the standard curve, or blank diluent brought
the total volume to 310 µL/well. The plates were read at a wavelength
of 595 nm at 24 hours and sample concentrations were determined by
linear regression.
Tumor cell line.
The MADB106 rat mammary tumor cell line (obtained from Dr John
Holcenburg, Department of Surgery, UCLA, Los Angeles, CA)
was initially developed by IP injections of
7,12-diemethylbenz[ ]anthracene into Fischer rats. Tumor was
excised and minced. Tumor cells were separated from tumor stroma and
injected into the right hind flank of the rats. Tumors were measured at
two perpendicular planes using a tissue caliper. Tumor volumes were
calculated from the formula: TV = 4/3  r3 where r = (diameter 1 + diameter 2)/4. Tumor growth inhibition (TGI) was
calculated: TGI = 1 Tvtreatment/TVcontrol × 100.
Statistical methods.
Analysis of variance was used to test the significance of differences
in hematocrit levels, rat weights, blood, tumor and liver folate
levels, and the efficacy of chemotherapy as influenced by folate
status. If a significant F value was found, Fisher's least significant
difference test was used to compare means. Tumor size and day were
transformed with a natural log function. Hierarchical linear modeling
procedures were used to examine the data.15 At the first
stage, each rat gave rise to a linear regression line between Log
(Tumor Size) and Log (Day) with an intercept and slope. At the second
stage, these intercepts and slopes were examined as a function of the
four diet groups. The slopes of the linear regression lines were
compared using a Fisher protected t type approach.15 Rat
survival in the toxicity study was analyzed by the Log-Rank test.
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RESULTS |
Our intent in these experiments was to study a range of folate status
in mammals, but to avoid extreme folate deficiency and thereby more
closely approximate the typical clinical situation. Rats maintained for
6 weeks on the folate replete diet, the low folate diet, the very low
folate diet, or the folate replete diet supplemented with folic acid,
50 mg/kg dissolved in 8.4% sodium bicarbonate solution and injected IP
daily, grew at the same rate (the mean weights of the groups were
within 2 g of each other on day 42) and were not anemic, but developed
evidence of progressively severe tissue deficiency of the vitamin
(Fig 1). There was a significant difference
among the three dietary groups (P  .005) for all three tissues, except between low folate and very low folate serum samples (P = .07).
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| Fig 1.
Folate levels, as determined by the L casei
method, in whole blood, serum, and liver in rats maintained for 6 weeks
on a folate replete diet containing 2 mg/kg folic acid ( ), a low
folate diet containing no folate ( ), or a very low folate diet
consisting of no folate plus 1% succinyl sulfathiazole ( ). There
was a significant difference (P .005) among the three
dietary groups for all three tissues, except between low folate and
very low folate serum samples (P = .07). SD, standard
deviation.
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After 6 weeks on the special diets described above, the four groups of
six animals each were inoculated subcutaneously with MADB106 rat
mammary tumor (1 × 105 viable cells in a 0.2-mL
suspension). The rats were examined daily and, when palpable, the
tumors were measured in 2 dimensions. Figure 2 shows that tumor growth rate
slowed progressively with decreasing amounts of folate intake.
Comparison of the slopes of the linear regression line between Log
(Tumor Volume) and Log (Day) showed that the rate of tumor growth over
time is diet-dependent (P < .05), and that folate
supplementation, even at the high levels used in these experiments, did
not significantly increase tumor growth rate compared with tumors in
folate replete rats (inset, Fig 2). However, folate deficiency of
moderate or marked degree significantly retarded the tumor growth rate
compared with folate replete or supplemented animals.
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| Fig 2.
Growth of MADB106 mammary tumor in rats maintained on
diets of varying folate content. After 6 weeks on the dietary
conditions indicated, tumor cells were injected subcutaneously into six
animals per group. Tumor volumes were measured by calipers. Insert:
Tumor volume and day plotted on natural log scales. At a significance
level of 5%, the slopes for the high folate diet were larger than the
low and very low folate diets, but not the folate replete diet. The
slopes for the folate replete diet were larger than the low folate
diet, but not the very low folate diet. The slopes for the very low
folate diet were larger than the low folate diet as a group.
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The folate levels in the tumors and livers from animals in the
different folate groups are shown in Table
1. Both tumor and liver folate levels progressively decreased with
decreasing dietary folate intake, but liver folate was higher than
tumor folate in each dietary group. All tumor folate levels were
significantly different from each other, at P .05, except
for the low folate versus very low folate groups. Similarly the
differences between hepatic folate levels were significant (P .02) except for the low folate versus very low folate groups. The
tumor and liver folate levels were correlated, with
r2 = 0.93, P < .05.
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Table 1.
Folate Levels, as Measured by the L casei Method
in MADB106 Mammary Tumors and Livers From Rats Maintained on Different
Folate Intakes
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Histologic examination of the tumors from the different folate groups
showed poorly differentiated carcinoma, with abundent necrosis, and
variable numbers of mitotic figures. There was no evidence of
megaloblastosis. No pathologic distinction could be discerned among
tumors differing in folate status.
To investigate the effect of folate status on the efficacy of
chemotherapy, weanling Fischer 344 rats were divided into three groups
of six animals each and maintained on a low folate diet, a folate
replete diet, or the latter diet supplemented with folic acid, 50 mg/kg
IP daily. After 7 weeks, MADB106 Mammary Tumor was injected
subcutaneously (5 × 105 cells/0.5 mL). When tumor was
palpable, the rats received cyclophosphamide 50 mg/kg, doxorubicin 5 mg/kg, 5-fluorouracil (5-FU) 50 mg/kg, or 0.9% NaCl solution IP. The
planned course of treatment was to repeat the same medications 4 and 8 days later. However, we found that the folate-deficient rats were much
more sensitive to the side effects of chemotherapy. After only two of
the planned three treatments, the condition of the animals in this
group rapidly deteriorated and the third treatment was not given. Of
the folate-deficient animals treated with two doses of
cyclophosphamide, two of six died (33% mortality). In contrast, there
was a 33% mortality after three courses of cyclophosphamide in the
folate-replete group, but no mortality in the folate-supplemented rats
treated with three injections of cyclophosphamide. After three
injections of 5-FU, there was one death in the folate-supplemented
group (17% mortality), but none in the folate-deficient or replete
dietary groups. There were no deaths among the three dietary groups
treated with doxorubicin.
To compare the efficacy of chemotherapy under different dietary
conditions, tumor inhibition as a percentage of control (0.9% NaCl
solution-injected rats) was calculated 96 hours after the second
injection of chemotherapy (just before the scheduled third injection).
Figure 3 shows that the TGIs for
cyclophosphamide were 53%, 98%, and 97% in the low folate, replete,
and high folate rats, respectively. For 5-FU, the TGIs were 46%, 49%,
and 66%, and for doxorubicin the TGIs were 25%, 55%, and 61%,
respectively. Using analysis of variance, the difference between the
folate-deficient animals treated with cyclophosphamide and the
folate-replete or supplemented rats was significant (P = .048).
The P values for 5-FU (.678) and doxorubicin (.442) were not
significant. These results suggest that tumors in folate-deficient
hosts are relatively resistant to cyclophosphamide, and that the
efficacy of this drug almost can be doubled by correcting folate
deficiency.
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| Fig 3.
Inhibition of MADB106 mammary tumor growth by
chemotherapeutic drugs in rats of varying folate status. (), Regular
diet; (), low folate; ( ), high folate. After 7 weeks on the
indicated diet conditions, tumor was injected subcutaneously and six
rats per group were treated with cyclophosphamide 50 mg/kg, 5-FU 50 mg/kg, doxorubicin 5 mg/kg, or vehicle alone. Two injections, 96 hours
apart, were given when the tumors were palpable. Ninety-six hours after
the second injection, tumor growth inhibitions were calculated. Using
analysis of variance, the difference between the folate-deficient
animals treated with cyclophosphamide and the folate-replete or
supplemented rats was significant (P = .048). The P
values for 5-FU (.678) and doxorubicin (.442) were not significant.
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Because the efficacy studies described above indicated that folate
status also might influence the toxicity of chemotherapeutic drugs,
further specific investigation of drug toxicity was performed. Weanling
Fischer 344 rats were divided into three groups of six animals each and
maintained for 7 weeks on the low folate diet, a folate replete diet,
or the latter diet supplemented with folic acid injections.
Cyclophosphamide 62.5 mg/kg, 5-FU 75 mg/kg, or doxorubicin 7.5 mg/kg
were injected on days 1, 5, and 9 (50, 55, and 59 days after beginning
the special diets). The animals were weighed daily and observed for
signs of toxicity: loss of grooming behavior, lethargy, and loss of
righting reflex. As shown in Fig 4, there
were dramatic differences in survival in rats receiving cyclophosphamide or 5-FU related to folate status, with
folate-supplemented animals doing better than folate replete animals,
and both groups demonstrating better survival than folate-deficient
rats. Thus, in the cyclophosphamide-treated group, all of the
folate-deficient animals were dead by day 12, while the majority of the
high folate animals survived until the end of the experiment, 1 week
after the last injection of chemotherapy. Similarly, there were no
deaths in the high folate animals treated with 5-FU, while two thirds of folate-deficient rats treated with this drug died by day 12. These
differences were statistically significant (P = .0084 for cyclophosphamide, P = .025 for 5-FU) by the Log-Rank test. In contrast, doxorubicin-treated rats did not show a relationship between
survival and folate status: the folate-supplemented rats did best, the
folate-deficient group was intermediate, and the folate-replete group
did the worst (P = .12). Analysis of variance indicated no
significant differences among the weights of the dietary groups treated
with cyclophosphamide, but high folate rats lost less weight than other
dietary groups after treatment with 5-FU (P = .0143) and
doxorubicin (P = .0067) (data not shown). Measurements of liver
folate levels in rats supplemented with folic acid indicated that
chemotherapy with these three drugs did not change tissue levels of the
vitamin compared with untreated control animals (data not shown).
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| Fig 4.
Effect of folate status on the toxicity of cancer
chemotherapy. Three groups of 18 rats each were maintained on the
indicated folate diets. After 7 weeks, six animals from each group were
treated with either cyclophosphamide 62.5 mg/kg (top), 5-FU 75 mg/kg
(middle), or doxorubicin 7.5 mg/kg (bottom). Drugs were injected three
times at 96-hour intervals (arrows). Survivals were significantly
different for cyclophosphamide (P = .0084) and 5-FU
(P = .025), but not for doxorubicin (P = .12) by
the Log-Rank test.
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DISCUSSION |
The results of these experiments indicate that nutritional folate
status influences the efficacy and toxicity of cancer chemotherapy in
rats. The extent of this influence varied by chemotherapeutic agent.
Cyclophosphamide, a bifunctional alkylating agent, was only half as
effective at inhibiting the growth of a rat mammary tumor and was much
more toxic in folate-deficient rats. Although 5-FU and doxorubicin
tended to be less effective at controlling tumor growth in
folate-deficient rats, these effects were not statistically
significant. The toxicity of 5-FU was significantly greater in
folate-deficient rats than in folate replete or supplemented rats,
while there was no clear effect of folate status on the toxicity of
doxorubicin.
Considering the large number of patients who receive chemotherapy each
year and the substantial number of these individuals who are likely to
have a nutritional abnormality of folate metabolism, it is surprising
that so little attention has been paid to the interactions of
chemotherapeutic agents and folate. Parchure et al16 found
that high doses of folate potentiated the cytotoxicity of methotrexate,
5-FU, cytosine arabinoside, or mitomycin C against P388 lymphocytic
leukemia in mice and prolonged survival, possibly by changes in purine
and pyrimidine supplies. In contrast, folate supplementation (5 mg/day) of children with acute lymphoblastic leukemia in
remission increased their tolerance of 6-mercaptopurine and raised a
concern that folate supplements might interfere with therapy.17 The ability of folate cofactors to enhance the
cytotoxicity of 5-FU by forming a stable complex that inhibits
thymidylate synthetase is well described,18 and folate
levels are known to affect the efficacy and toxicity of 5-FU. For
example, Chéradame et al19 have shown that the
response of patients with head and neck cancer to 5-FU was correlated
with tumoral reduced folate pools. The distribution of reduced folates
was significantly higher for complete responders in comparison to
patients with a partial or no response.19 Recent studies in
a dietary folic acid-depleted mouse model indicated that C3H mouse
mammary adenocarcinomas were somewhat less responsive to 5-FU alone
compared with folate replete animals.20 Leucovorin
administration 1 hour before 5-FU suppressed tumor growth 80% in
folate-depleted mice. However, the administration of leucovorin at an
improper time before 5-FU (12 hours) not only did not potentiate, but
actually resulted in tumor growth stimulation.20 Similarly,
studies of the effects of folinic acid in 5-FU induced killing of human
tumor cell lines in vitro found that the cell of origin, the dose, and
the duration of exposure to folinic acid all influenced
cytotoxicity.21 The addition of very high doses of folic
acid (125 mg/kg) increased the toxicity of 5-FU in mice.16 In humans, stomatitis and diarrhea tend to be more frequent when folinic acid is added to 5-FU than with 5-FU alone and is the dose-limiting toxicity.22 However, hematologic toxicity
tends to be less with the combination of folinic acid/5-FU than with 5-FU alone.22 These studies emphasize the complex
interactions of folate status and chemotherapy.
A further example of this complexity is the interaction of folate
status and antifols. In 1962, Potter and Briggs7 reported that folate-deficient mice were extremely sensitive to amethopterin. More recently, this sensitivity was confirmed with
5,10-dideazatetrahydrofolic acid (DDATHF, Lometrexol). This agent
interferes with de novo purine synthesis by inhibition of the two
folate-dependent enzymes along that pathway, glycinamide ribonucleotide
and aminoimidazole carboxamide transformylase. Mice fed a low folate
diet for a short period became more than 1,000-fold more sensitive to
the lethality of DDATHF than animals fed a standard laboratory
diet.23 Moderate folate supplementation (about 6 mg/kg/d orally) allowed complete suppression of C3H
mammary adenocarcinoma without drug toxicity.23 However, at
high levels of folic acid intake (about 2,000 mg/kg/d orally), the antitumor activity of the drug was completely
blocked.23 The applicability of these preclinical studies
in rodents to humans is indicated by the observation that dietary
folate supplementation of phase I patients has been reported to reduce
DDATHF drug toxicity, allow further dose escalation, and preserve
antitumor activity.24 Thus, the effect of folate status on
the efficacy and toxicity of chemotherapy appears to vary depending on
the drug, the tumor cell type, and the folate level. In some
circumstances, the correction of folate deficiency or additional
supplementation may be beneficial, while in other circumstances, it may
be detrimental.
Further complicating the issue is the fact that folate levels modulate
tumor behavior independent of any effects on chemotherapy. The results
presented here support older observations that dietary folate
deficiency inhibits the growth of tumors.6,7 We found that
nutritional folate deficiency of moderate or marked degree significantly slowed rat mammary tumor growth compared with animals on
a folate replete diet. However, additional supplementation with large
amounts of folic acid daily did not significantly increase the rate of
tumor growth compared with rats ingesting the folate replete diet
alone. This observation is consistent with in vitro studies indicating
that supplementation with folic acid above levels required for cell
replication does not shorten the cell doubling time (reviewed in
Branda25). Therefore, it appears that correction of folic
acid deficiency will release the inhibition of tumor growth rate, but
folate supplementation does not accelerate the rate.
Measurement of folate levels showed that tumor levels were lower than
hepatic levels, but that the two levels were correlated. The folate
status of the MADB106 mammary tumor recovered from rats on the folate
replete diet, 0.091 ± 0.074 µg/g wet weight, was comparable to
folate levels previously published for Walker carcinosarcoma 256 in
rats (0.37 ± 0.13 µg/g tissue) and for a variety of human cancers
(0.05 to 0.5 µg/g of tumor).6,8 Rosen and
Nichol6 concluded that the folic acid content of Walker
carcinosarcoma 256 was less influenced than the liver by the dietary
level of the vitamin because of the higher capacity of the liver to
store folate. On the other hand, Gailani et al8 found that
in patients on a folate-deficient diet, the rate of folate depletion in
the tumor tissue roughly paralleled the rate of depletion in liver and
blood. More recently, Raghunathan et al26 reported that
accumulation of folate compounds was approximately simultaneous in
plasma and mammary adenoncarcinoma in mice, but delayed in liver. They
found more active metabolism of folinic acid in the liver than in the
tumor.26 It appears, then, that generally there is a direct
relationship between blood, hepatic, and tumor folate levels, but in
some neoplastic tissues, the folate level may be low in the face of
normal blood and adjacent tissue folate levels.27
Taken together, our studies and those of others indicate that folate
status influences the efficacy and/or the toxicity of some, but
not all chemotherapeutic drugs. It also seems likely that nutritional
folate deficiency retards the growth of tumors. Therefore, correction
of folate deficiency may be detrimental to the host if the tumor cannot
be treated effectively. Alternatively, if effective therapy is
available, our studies suggest that correction of folate deficiency can
be beneficial. We found that cyclophosphamide was nearly twice as
effective, with less toxicity, in folate replete compared with
folate-deficient animals. Because slowly dividing cells are relatively
resistant to chemotherapy, the improved efficacy of cyclophosphamide in
folate-supplemented animals may be secondary to increased proliferation
compared with folate-deficient tumor cells. We recognize that rodents
may not be an ideal model for the study of folate-chemotherapy
interactions.28 Therefore, extrapolation of these results
to humans should await controlled clinical trials.
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FOOTNOTES |
Submitted March 10, 1998;
accepted June 2, 1998.
Supported by Grants No. CA 41843 and P30CA22435 from the National
Cancer Institute, Bethesda, MD.
Address reprint requests to Richard Branda, MD, Genetics
Laboratory, University of Vermont, 32 N Prospect St, Burlington, VT
05401.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
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ACKNOWLEDGMENT |
We thank Dr Takamaru Ashikaga for his assistance with the statistical
analyses and Dr John Lunde for his review of the tumor histology.
| |
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Abstract
Introduction
Abstract