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Phospholipid Fatty Acid Composition and Diamine Oxidase Activity of Intestinal Mucosa From Rats Treated With Irinotecan Hydrochloride (CPT-11) under Vegetable Oil–Enriched Diets: Comparison Between Perilla Oil and Corn Oil

From the Division of Surgical Metabolism, Faculty of Health Science, Kobe University School of Medicine, Kobe, Japan

Correspondence: Makoto Usami, MD, PhD, Division of Surgical Metabolism, Faculty of Health Science, Kobe University School of Medicine, 7–10-2 Tomogaoka, Suma-ku, Kobe 654-0142, Japan. Electronic mail may be sent to musa{at}ams.kobe-u.ac.jp.

Background: Irinotecan hydrochloride (CPT-11), a topoisomerase I inhibitor highly effective for various cancers, has its dosage limited by diffuse mucosal damage with increased prostaglandin (PG) E₂. However, an analysis of intestinal phospholipid fatty acid composition after CPT-11 treatment has not been reported. This study aimed to evaluate intestinal phospholipid fatty acid composition in relation to intestinal mucosal integrity and plasma and mucosal PGE₂ levels after CPT-11 treatment. The effect of dietary vegetable oil supplementation, perilla oil vs corn oil, was also evaluated. Methods: Intestinal phospholipid fatty acid composition, PGE₂ level, mucosal diamine oxidase (DAO) activity, diarrhea, and blood tests were evaluated in rats injected with CPT-11 under a conventional diet. The same parameters were compared among 3 different dietary vegetable oil supplementations: perilla oil, corn oil, and a 1:3, respectively, mixture with a semisynthetic diet during 14 days. Results: CPT-11 treatment caused severe diarrhea, and intestinal mucosal fatty acid composition changed with increased PGE₂ level and decreased DAO activity. Decreases in eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and EPA/arachidonic acid (AA) ratio in colonic mucosa were observed. Perilla oil increased -3 polyunsaturated fatty acids, -linolenic acid, EPA, and EPA/AA ratio and decreased plasma PGE₂. But the amounts used were not enough to attenuate intestinal damage from CPT-11 treatment. Conclusions: CPT-11 induced changes of intestinal mucosal fatty acid composition with increased PGE₂ level and decreased intestinal integrity; perilla oil shows the possibility of being able to attenuate those changes.

Controlling drug resistance and symptoms in cancer patients by essential fatty acids supplementation is a major concern in clinical nutrition.^1,2 However, fatty acid status with cancer chemotherapy or evidence of abnormalities in the lipid metabolism in advanced cancer patients has not been well characterized.³ Beneficial effects of -3 fatty acids supplementation imply the presence of an imbalance between essential -6 and -3 fatty acids or a deficiency of -3 fatty acids. Indices of fatty acid status may have prognostic value for selective patients who are likely to obtain benefits from supplementation; however, to date, supplementation has not been prospectively examined according to a determined fatty acid status. Detailed indices of fatty acid status of the lesion in relation to severe side effects due to effective cancer chemotherapy are also of interest for assessing the efficacy of supplementation protocols to control the adverse effects of cancer chemotherapy.

Irinotecan hydrochloride (CPT-11) (camptosar, irinotecan) is a topoisomerase I inhibitor that has been shown to be highly effective in treatment of colonic, gastric, pancreatic and non–small cell lung cancers. However, the dosage of CPT-11 is limited by the toxicity of diffuse mucosal damage in the large intestine and delayed-onset diarrhea. Late diarrhea, which usually occurs >24 hours after the CPT-11 injection, is National Cancer Institute grade 3 or 4 in up to 31% of the patients.⁴ CPT-11 administration is associated with increased colon prostaglandin (PG) synthesis in both in vivo and ex vivo models.^4,5 After CPT-11 treatment, increased PGE₂ has been reported to have a key role in water and electrolyte balances in the colon.

Recently, several reports have indicated the importance of controlling colonic or hepatic PGE₂ production by different therapeutic modalities in CPT-11 treatment. Hardman et al⁶ reported a reduction of side effects of CPT-11 using -3 fatty acids product. They indicated that fish oil supplementation with CPT-11 for MCF7 breast carcinoma in mice enhanced the anticancer effect and ameliorated intestinal side effects, indicating degeneration and necrosis of villi and crypt cells.⁷ A high concentration of -3 polyunsaturated fatty acids (PUFA) products reduced liver hypertrophy side effects of CPT-11 in mice⁶; however, they showed only changes of eicosapentaenoic acid (EPA, C20:5 -3) and docosahexaenoic acid (DHA, C22:6 -3) composition in the liver and did not indicate the fatty acid composition of the intestine. Kase et al⁸ reported that Hange-shashin-to, an inhibitor of cyclooxygenase (COX)-2 belonging to a Kampo medicine, prevents diarrheal side effects of CPT-11 via a reduction of the colonic PGE₂ level. Trifan et al⁹ reported that a selective COX-2 inhibitor, celecoxib, reduces diarrheal side effects and enhances the antitumor efficacy of CPT-11 in 2 mouse tumor models; this under the general observation of a number of studies that have shown that COX-2 is overexpressed in many forms of human tumors suggests that COX-2 inhibition may be useful in the treatment of cancer.

However, an analysis of intestinal phospholipid fatty acid composition after CPT-11 treatment combined with intestinal integrity and colonic PGE₂ level has not previously been presented. The first purpose of this study is to evaluate intestinal phospholipid fatty acid composition after CPT-11 treatment under a conventional diet. The second is to compare the effect of different dietary vegetable oil supplementations, perilla oil vs corn oil and a 1:3, respectively, mixture with a semisynthetic diet, on CPT-11-induced intestinal changes after the Mitsugi et al¹⁰ report. Mitsugi et al¹⁰ indicated a reduction of gastrointestinal toxicity caused by methotrexate treatment by feeding a 1:3 mixture of perilla oil and corn oil with soybean protein. Perilla oil is rich in vegetable -3 PUFA, especially -linolenic acid (ALA, C18:3 -3). ALA is converted to EPA or DHA after enzymatic desaturation and elongation in the liver. No information is currently available on the effect of perilla oil on CPT-11-induced diarrhea and mucosal damage.

	MATERIALS AND METHODS

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
Animal and Diet Preparation
Fifty male Sprague-Dawley rats were obtained from Japan SLC (Hamamatsu, Japan). All animals were fed standard diets, CRF-1 (Charles River Japan, Osaka, Japan) for a week in an animal room maintained at a temperature of 23 ± 3°C and a relative humidity of 55% ± 15% with a 12-hour light-dark cycle. One week before CPT-11 treatment, rats weighing 224.5 ± 0.4 g were randomly divided into 5 groups of 10 animals each and kept under the same diet conditions until killing. Two groups of rats were fed a conventional diet, CRF-1 including 6% crude oil, as the control (C) group. The other groups of rats were fed a semisynthetic diet (AIN-93M, Oriental Yeast Co, Osaka, Japan) with 10% vegetable oil consisting of corn oil, the -6 group or perilla oil, the -3 group or their 3:1 mixture, the mix group (vegetable oils were donated by the Research Institute of Life Science, Snow Brand Milk Products Co, now EN Otsuka Pharmaceutical Co, Hanamaki, Japan). Fatty acid composition of the diet is indicated in Table I. All the experimental diets were prepared by the Oriental Yeast Co, packed in airtight containers filled with nitrogen and stored at 4°C until use.¹¹

CPT-11 was obtained as irinotecan hydrochloride (Yakult Honsha Co, Osaka, Japan) and prepared according to the manufacturer's directions. Rats were given CPT-11 or vehicle at an IV dose of 60 mg/kg from the tail vein once daily for 4 successive days. The specific treatment schedule for CPT-11 injections in the rat experiment was selected in accord with the results in Kurita et al¹² and Takasuna et al¹³ Rats were kept in a metabolic cage while food intake and severity of diarrhea and body weight changes were monitored during the experimental period (5–7 days from the first administration). Stainless wire mesh (20 mesh) was installed on the floor of the metabolic cage, and the severity of diarrhea was scored as follows: 1 (normal; normal stool), 2 (soft; adherent to the mesh with stool shape), 3 (muddy; passed through the mesh with no stool shape), and 4 (watery; completely passed through the mesh and mixed in the urine container) after the Hayashi et al¹⁴ report. The same experimental procedure was repeated 2 times, with each of the 5 groups consisting of 10 rats.

Rats were killed under pentobarbital anesthesia 1 week after the start of the CPT-11 injection. After blood sampling from the aorta, the intestine was removed, rinsed with cold saline, and 3 parts of 5-cm length consisting of proximal jejunum, terminal ileum, and colon were frozen in liquid nitrogen and kept under –80°C until analysis. Serum biochemical data were measured by automated analyzer (type 705, Hitachi Co, Tokyo, Japan). Hematologic data were measured by automated hematology analyzer (Sysmex K-1000, Sysmex Co, Kobe, Japan). Part of the intestinal tissues (ileum and colon) were fixed in 10% neutral buffered formaldehyde, embedded in paraffin wax, and stained with hematoxylin and eosin for light microscopy.

Parts of the intestinal mucosa (ileum and colon) were thawed, scraped off with a slide glass, and used for analysis of fatty acid composition, diamine oxidase (DAO) activity, and PGE₂ concentration.

Gas chromatography. Samples of mucosa were homogenized in 1 mL of ice-cold 25 nmol/L phosphate buffer (pH 7.4), and lipids were extracted with chloroform: methanol:water (2:1:0.8, vol/vol) containing 0.01% butylated hydroxytoluene after Bligh-Dyer method.¹⁵ Phospholipids were separated using thin-layer chromatography (20-x-20-cm silica gel 60/Kieselgur F₂₅₄ TLC plate, Merk, Tokyo, Japan) and scraped off, then evaporated to dryness 3 times with methanol. Phospholipid samples were hydrolyzed, methylated, evaporated to dryness, and then filled with nitrogen gas and kept under –20°C. Fatty acid methyl esters (dissolved in methyl acetate) were separated by gas chromatography in a Shimadzu GC-14A gas chromatograph (Shimadzu, Kyoto, Japan) fitted with a 50-m-x-0.25-mm liquid phase CP-Sil 88 capillary column. Helium at 1.0 mL/min was used as the carrier gas, and the split/splitless injector was used in the split mode, with a split ratio of 100:1. Injector and detector temperature were both 250°C, and the column oven temperature was programmed from 160°C to 192°C at 4°C/min, followed by a 10 minutes hold at 192°C, and then 192°C to 230°C at 4°C/min. The separation was recorded with a Shimadzu C-R4AX recorder, and quantitative data were recorded with a Shimadzu C-R4AX recording integrator. Fatty acids were identified by comparison with previously run standards for caprylate, caprate, laurate, myristate, palmitate, stearate, arachidate, cis-11-eicosenoate, docosanate, eructate, lignocerate, and nervonate.

View larger version (14K): [in this window] [in a new window]   FIGURE 1. Diarrhea score in rats after IV irinotecan hydrochloride (CPT-11) injection: 1 (normal; normal stool), 2 (soft; adherent to the mesh with stool shape), 3 (muddy; passed through the mesh with no stool shape) and 4 (watery; completely passed through the mesh and mixed in the urine container).

PGE₂ assay. Mucosal PGE₂ concentration was measured after Kobayashi et al¹⁷ using enzyme immunoassay (EIA) kits (Amersham Biosciences Corp, Piscataway, NJ) in accordance with the manufacturer's manual. Briefly, mucosa was homogenized on ice using a Teflon homogenizer in ice-cold 25 nmol/L phosphate buffer (pH 7.4) and centrifuged at 3000 x g for 10 minutes. The supernatant fraction was divided for PGE₂ extraction and protein measurement described previously. PG acetic acid ethyl ester solution was extracted by Amprep C18 mini-column and measured with an EIA kit. Plasma PGE₂ concentration was measured with the same EIA kit and results expressed as ng/mg protein.

Statistical Analysis
Data were expressed as means ± SD. The results for all the tests were evaluated by Fisher's protected least significant difference (PLSD) multiple comparison test to identify significant differences among multiple samples (Statview statistical software package; version 4.51.1; Abacus Concepts, Berkeley, CA). The statistical significance was assured when the p value was < .05.

	RESULTS

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
In the first experiment, 1/4 rats in the C group, 4/5 rats in the -6 group, 4/5 rats in the -3 group, and 5/5 rats in the mix group died with melena by the sixth day after starting CPT-11 injection. Surviving rats were killed on day 12 (ie, 5 days after starting CPT-11 injection) in the second experiment to avoid sample loss.

View larger version (14K): [in this window] [in a new window]   FIGURE 2. Percent body weight change and total diet consumption in rats after IV irinotecan hydrochloride (CPT-11) injection; *p < .01 vs CPT-11 groups and #p < .05 vs C group with CPT-11.

View larger version (9K): [in this window] [in a new window]   FIGURE 4. Diamine oxidase activity of the intestinal mucosa from rats after IV irinotecan hydrochloride (CPT-11) injection; *p < .05, #p < .05 vs CPT-11 -6 group.

View larger version (16K): [in this window] [in a new window]   FIGURE 5. Prostaglandin E2 concentration in the intestinal mucosa from rats after IV irinotecan hydrochloride (CPT-11) injection; *p < .05, #p < .05.

View larger version (44K): [in this window] [in a new window]   FIGURE 3. Representative histology of colonic mucosa stained with hematoxylin and eosin. Original magnification 200x. A, C + vehicle, B, C + CPT-11, C, -6 + CPT-11, D, mix + CPT-11, E, -3 + CPT-11.

View larger version (15K): [in this window] [in a new window]   FIGURE 6. Relationship between prostaglandin E2 concentration and diamine oxidase activity in intestinal mucosa from rats after IV irinotecan hydrochloride (CPT-11) injection.

Data in Tables II, III, and IV were compared among groups fed the same diet. In the CPT-11 treatment group, there was a significant decrease in triglyceride level, but no change in total cholesterol, nonesterified fatty acid, and phospholipid levels in the blood (Table II). Fatty acid composition of the intestinal mucosa in the normal rats was comparative to the phospholipid fraction in small intestine and colonic mucosa of rats reported by Korotkova and Strandvik.¹¹ Changes in phospholipid fatty acid composition of colon mucosa were more remarkable than those of the ileum (Tables III, IV). CPT-11 treatment increased stearic acid (SA, C18:0) to 1.24-fold and decreased arachidonic acid (AA, C20:4 -6) to 0.85-fold, EPA to 0.41-fold, and DHA to 0.67-fold (p < .01). It decreased -3 PUFA to 0.63-fold, the EPA/AA ratio to 0.5-fold, PUFA to 0.84-fold, and unsaturation index to 0.83-fold, and increased the -6/-3 ratio to 1.36-fold and saturated fatty acids to 1.13-fold.

Effect of Dietary PUFA With the Semisynthetic Diet on CPT-11-Treated Rats
The severity of diarrhea after CPT-11 treatment was worse in the PUFA administration groups with the semisynthetic AIN-93M diet than those in the CPT-11 treatment group with the conventional CRF-1 diet (Figure 1). They began suffering grade-4 watery diarrhea from the third day after CPT-11 treatment in comparison with the C group indicating 75% in grade 1 and 25% in grade 2 on the same day. There was no difference in the degree of diarrhea among the different PUFA groups (Figure 1).

Decreases in percent body weight after CPT-11 injection were same among 4 groups (Figure 2). There were significant decreases in dietary intake among 4 groups after CPT-11 injection, and, in particular, the -6 and -3 groups showed significant differences compared with the C group (p < .05). Disturbance in hemopoiesis and decreased spleen weight were observed (p < .01, Table II). Increased total protein, blood urea nitrogen (BUN), and creatinine and red blood cell counts with increased lung and kidney weight suggested hemoconcentration and renal dysfunction due to severe diarrhea. Also decreased triglyceride and increased total cholesterol, phospholipid, and nonesterified fatty acid levels were noted. Those changes were similar in the 3 different PUFA supplement groups, but were more serious than those in the conventional diet group. Intestinal mucosal injury in the -6 group was more severe than that in the C group after CPT-11 treatment. Mucosal surface epithelium and goblet cells in the crypt almost disappeared, and the crypt lumen showed cystic dilation. Erosion, teleangiectasis, and remarkable mucosal bleeding and inflammatory cell infiltration in the submucosal layer were observed (Figure 3). But the crypt structure and goblet cells were maintained, and bleeding was not observed in the -3 group. The mix group indicated an intermediate changes between those of the -3 and -6 groups. DAO activity in the ileum of the -6 group was lower than that of the C group, whereas that in the jejunum of the mix group was lowest (Figure 4). Plasma PGE₂ level in the -6 group (p < .05) and that of the colon mucosa in the mix group were highest, respectively, among the 4 groups after CPT-11 treatment (Figure 5).

Decreased plasma total cholesterol and phospholipid levels in the perilla oil group compared to the corn oil group indicate the effectiveness on lipid metabolism, even at this amount. Phospholipid fatty acid composition in the ileum and colon mucosa between the 3 PUFA groups was different. EPA/AA ratio in the -3 group was higher, and the -6/-3 ratio was lower than that in the -6 group (Table IV). SA, ALA, and EPA in the -3 group were higher than those in the -6 group (p < .05–.01). The increase in -3 PUFA in the ileum was more remarkable than that in the colon.

	DISCUSSION

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
This is the first report to indicate intestinal mucosal phospholipid fatty acid composition changes under CPT-11 treatment. CPT-11 administration induced severe diarrhea, decreased intestinal integrity reflected by a decrease in DAO activity and an increase in PGE₂ level, and induced altered intestinal mucosal phospholipid fatty acid composition, especially in colonic mucosa. The apparent negative correlation between intestinal DAO activity and PGE₂ level supports that a PGE₂ level increased by CPT-11 is one of the mechanisms that decreases intestinal integrity. Statistically significant differences, an increase in total saturated fatty acids and a decrease in both total monounsaturated fatty acids and PUFA were observed, but those changes are less remarkable than the changes in the -3 or -6 PUFA fractions. Decrease in -3 PUFA, EPA, DHA, and the EPA/AA ratio and increase in the -6/-3 ratio were observed. Furthermore, the decrease in -3 PUFA corresponds to an increased PGE₂ level under CPT-11 treatment. Inflammatory eicosanoids such as PGE₂ are produced from AA, whereas EPA competitively inhibits PGE₂ formation and results in the formation of less inflammatory PGE₃.

Our results indicate that changes in colonic phospholipid fatty acid composition are more characteristic than those in the ileum; however, Korotkova and Strandvik¹¹ reported that changes in the ileum and colon are similar under dietary deficiency of essential fatty acids. Decrease in EPA (0.41-fold) after CPT-11 treatment is less than the decrease of 0.2-fold ALA after 7 weeks' dietary deficiency in essential fatty acid.¹¹ The reason for the differences between this study and the Korotkova and Strandvik¹¹ report is considered to be the result of direct colonic mucosal injury by the active metabolite of CPT-11; that is 7-ethyl-10-hydroxy camptothecin (SN-38), in the colonic lumen because β-glucuronidase in intestinal microflora deconjugates glucuronized SN-38, which is glucuronized in the liver and excreted to the intestine via the biliary tract, to the active form of SN-38.¹³ Slight abnormalities in lipid metabolism, only observed from plasma triglyceride levels, in this model also support the specificity of the intestinal phospholipid fatty acid composition change from the presence of SN-38 in the colonic intestinal lumen.

Phospholipid fatty acid composition under cancer chemotherapy has rarely been reported, but the abnormality found in this study is quite different than that reported in the study by Pratt et al.³ In their study, high-dose chemotherapy consisting of cyclophosphamide, mitoxantrone, and vinorelbine after induction chemotherapy with 5-fluorouracil, adriamycin, and cyclophosphamide for breast cancer patients increased EPA and DHA and decreased -6/-3 ratio of the neutrophils phospholipid fatty acid composition. They discussed the mechanism in reference to the Marra et al¹⁸ report indicating cytotoxic agents interfere with the metabolism of PUFA via modulation of 6 and 5 desaturase activities. Decreased -6/-3 ratio in patients or rats with tissue damage due to hypercytokinemia or severe burn is also reported.^3,19 Those differ from the results of this study. The exact mechanisms for CPT-11 treatment inducing changes of fatty acid composition and increasing -6/-3 ratio require future study.

In the second objective of the study, the effect of dietary -3 or -6 PUFA administration consisting of perilla oil, corn oil, or their 1:3 mixture was compared. Our results indicated that perilla oil attenuates plasma PGE₂ increase and mucosal damage observed in histologic findings. However, the amount of perilla oil might not be sufficient to produce any remarkable effects on mucosal PGE₂, DAO activity, diarrhea, weight loss, and organ dysfunction induced by CPT-11 administration. Changes in mucosal fatty acid composition indicating a 2-fold increase in ALA and EPA/AA ratio and a 3-fold increase in EPA in the -3 group of this study are comparative to the effect of perilla oil in azoxymethane-induced foci of colonic mucosa.²⁰ However, the extent of their changes in our study is less than those correlates in the Onogi et al²⁰ report. The difference agrees with the amount and duration of administration; that is, 10% perilla oil during 2 weeks in our study compared with the Onogi et al²⁰ report treating with 16% perilla oil during 6 weeks.^10,20

Perilla oil contains high ALA (57%) and low linoleic acid (LA, 13%). Decreased plasma total cholesterol and phospholipid levels in perilla oil–treated rats in comparison with corn oil–treated rats is in accordance with the report indicating that ALA appears to suppress gene expression of lipogenic enzymes or stimulate the fatty acid oxidation rate in the liver in rats.²¹ ALA is the fatty acid for starting -3 PUFA synthesis and is metabolized to EPA and DHA. These -3 PUFA have been reported to attenuate inflammation in human patients.²² Perilla oil feeding gives a lower AA level and higher EPA and DHA levels²³ and reduces eicosanoid production (PGE₂, leukotriene [LT] B4, and platelet activating factor) as has been reported by Ohhashi et al and Ohtsuka et al.^24,25

It may be necessary to give perilla oil for a longer period of time when correcting CPT-11 induced enteropathy. The same amount of perilla oil diet over 4 weeks lowered PGE2 production in leukocytes. An amount of 90 g/kg perilla oil, given by intravenous infuxion, reduced LTB4 and LTC4 production from intestinal mucosa in a rat with inflammatory bowel disease. This was 90% of the amount given in our experiments.²⁷ While our study did not show significant decreases in amino acids and total omega-6 fatty acids, Ohtsuka et al found significant effects after 4 weeks of administration.²⁵ Work by Mitsugi suggested that soybean protein may improve efficacy of perilla oil.¹⁰ It was suggested that anti-inflammatory properties of ALA would be potentiated by concurrent soybean protein, but not by casein.²⁶

Clinical trials must be conducted to determine whether the beneficial effects of -3 fatty acids supplements seen in experimental animals can be translated to patients undergoing cancer chemotherapy using CPT-11.

The study was supported by research grants from Otsuka Pharmaceutical Factory Inc, Naruto, Tokushima, Japan; Yakult Honsha Co, Tokyo, Japan; and Nihon Pharmaceutical Co, Tokyo, Japan.

We acknowledge the help of Shyozo Aoi, BS; Kazuo Hino, MS; Yuichi Kawano, PhD; Yasunori Kondo, PhD; Shinya Miki, MS; Yoichi Ohno, BS; Yosuke Kataoka, BS; and Tsuyoshi Nakamura, PhD, in the development of this project.

Received for publication September 20, 2004. Accepted for publication December 7, 2005.

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Journal of Parenteral and Enteral Nutrition, Vol. 30, No. 2, 124-132 (2006)
DOI: 10.1177/0148607106030002124


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