Irinotecan-induced Diarrhea Research Articles

Clinical observations on associations between the UGT1A1 genotype and severe toxicity of irinotecan.

Severe toxicity is commonly observed in cancer patients receiving irinotecan (CPT-11). UDP glucuronosyltransferase1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38 but the relationship between UGT1A1 and severe toxicity remains unclear. Our study aimed to assess this point to guide clinical use of CPT-11. 89 cancer patients with advanced disease received CPT-11-based chemotherapy for at least two cycles. Toxicity, including GI and hematologic toxicity was recorded in detail and UGT1A1 variants were genotyped. Regression analysis was used to analyse relationships between these variables and tumor response. The prevalence of grade III-IV diarrhea was 10.1%, this being more common in patients with the TA 6/7 genotype (5 of 22 patients, 22.7%) (p<0.05). The prevalence of grade III-IV neutropenia was 13.4%and also highest in patients with the TA 6/7 genotype (4 of 22 patients; 18.2%) but without significance (p>0.05). The retreatment total bilirubin levels were significantly higher in TA6/7 patients (mean, 12.75μmol/L) with compared to TA6/6 (mean, 9.92 μmol/L) with p<0.05. Our study support the conclusion that patients with a UGT1A1*28 allele (s) will suffer an increased risk of severe irinotecan-induced diarrhea, whether with mid-or low-dosage. However, the UGT1A1*28 allele (s) did not increase severe neutropenia. Higher serum total bilirubin is an indication that patients UGT1A1 genotype is not wild-type, with significance for clinic usage of CPT-11.

P3–105 - Randomized Study to Explore Indisetron for the Prevention of Acute-Onset Diarrhea, Nausea, Vomiting with IRIS/FOLFIRI

Background: Indisetron is a serotonin (5-hydroxytryptamine type 3) receptor antagonist that also antagonizes 5-hydroxytryptamine type 4 receptors. Indisetron tablets showed the non-inferiority to ondansetron tablets in terms of efficacy for preventing Chemotherapy-induced nausea and vomiting (CINV). Preclinical data showed indisetron significantly reduced the stool frequency in mice and the bowel frequency in dogs when administered irinotecan. We designed a pilot study compared the efficacy and tolerability of indisetron for irinotecan-induced diarrhea, nausea, and vomiting with granisetron.

Predicting hiCE inhibitors based upon pharmacophore models derived from the receptor and its ligands

Human intestinal carboxyl esterase (hiCE) is a drug target for ameliorating irinotecan-induced diarrhea. By reducing irinotecan-induced diarrhea, hiCE inhibitors can improve the anti-cancer efficacy of irinotecan. To find effective hiCE inhibitors, a new virtual screening protocol that combines pharmacophore models derived from the hiCE structure and its ligands has been proposed. The hiCE structure has been constructed through homology techniques using hCES1’s crystal structure. The hiCE structure was optimized via molecular dynamics simulations with the most known active hiCE inhibitors docked into the structure. An optimized pharmacophore, derived from the receptor, was then generated. A ligand-based pharmacophore was also generated from a larger set of known hiCE inhibitors. The final hiCE inhibitor predictions were based upon the virtual screening hits from both ligand-based and receptor-based pharmacophore models. The hit rates from the ligand-based and receptor-based pharmacophore models are 88% and 86%, respectively. The final hit rate is 94%. The two models are highly consistent with one another (85%). This proves that both models are reliable.

Abstract LB-160: Dual application of TLR5 agonist in cancer treatment: A single agent combines supporting care and antitumor activities

Abstract We have previously shown the strong radioprotective properties of TLR5 agonist flagellin in both mouse and non-human primate models (Burdelya et al., 2008, Science 320: 226–230). A pharmacologically optimized flagellin derivative, Protectan CBLB502, is currently at an advanced stage of development as a prospective radiation antidote for biodefense applications. By testing CBLB502 in combination with radiation treatment of experimental mouse tumors in vivo, we demonstrated that its tissue protection properties are limited to normal tissues with no tumor protection detected in any of numerous mouse tumor models. For example, injections of CBLB502 significantly reduced the severity of mucositis and dermatitis associated with local fractioned irradiation of the head and neck area of mice with syngeneic orthotopically grown head and neck carcinoma with no reduction of antitumor effect of experimental radiotherapy. On the contrary, use of CBLB502 led to enhanced tumor suppression by radiation and produced a detectable tumor suppressive effect even without irradiation. Similar results were obtained in s.c. grown syngeneic colon Wart tumors in rats. In this model, administration of CBLB502 reduced the severity of irinotecan-induced diarrhea, but did not interfere with the anti-tumor effect of the drug. Moreover, use of CBLB502 as a single agent had a pronounced antitumor effect in the majority of Wart tumor-carrying rats. Comparison of the effect of CBLB502 on in vivo growth of isogenic pairs of tumor cell lines differing in their TLR5 status showed that the antitumor effect of the TLR5 agonist is TLR5 dependent and is associated with tumor infiltration by immunocytes, presumably attracted following activation of TLR5 signaling in the tumor cells. Remarkably, CBLB502 caused an immunotherapeutic effect in TLR5-negative tumors growing as experimental metastases in the liver which was found to be the primary target of TLR5 agonist. The liver responds to CBLB502 injection by massive and rapid activation of NF-kB in all hepatocytes. This results in dramatic changes in the content of secreted factors, attraction of immunocytes and a strong reversible increase in liver resistance to a variety of toxic agents. Based on these results, we project clinical applications of CBLB502 as a bi-functional therapeutic agent with supporting care (protection of normal tissues from radio- and chemotherapy side effects) and immunotherapeutic activities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-160. doi:10.1158/1538-7445.AM2011-LB-160

Preliminary results of gentamycin combined with sodium bicarbonate for prevention of irinotecan-induced diarrhea

The aim of this paper was to observe the clinical effect of gentamycin combined with sodium bicarbonate for the prevention of irinotecan-induced diarrhea. A total of 98 patients with stage IV cancers were recruited and divided into a prevention group (52 patients) and a control group (46 patients). All patients received the chemotherapy including irinotecan. The prevention group received gentamycin and sodium bicarbonate before the use of irinotecan for 4 days; the control group did not receive any prevention. The use of gentamycin and sodium bicarbonate resulted in significantly higher stool pH (P<0.001), while the incidence of diarrhea by irinotecan was reduced (prevention group 13.70% versus control group 34.83%; P<0.001). Gentamycin combined with sodium bicarbonate appears to be useful in preventing the diarrhea induced by irinotecan and reducing the dosage of loperamide and fluid replacement.

The effect of Saccharomyces boulardii on reducing irinotecan-induced intestinal mucositis and diarrhea

To investigate the efficiency of Saccharomyces boulardii on irinotecan-induced mucosal damage and diarrhea in rats, fifty rats were randomized into three groups with 20 rats in two study groups and 10 rats in the control group. Control group did not receive any treatment. Irinotecan (60 mg/kg) alone was administered intravenously once a day for four consecutive days to the rats of Group A. Throughout the experiment, Group B rats were additionally given Saccharomyces boulardii (800 mg/kg) for 3 days before administration of irinotecan and 7 days throughout the experiment. Delayed diarrhea was more severe in Group A than Group B (P = 0.009). The weight loss was 34.7 +/- 3.8 mg for Group A, while it was 17.4 +/- 1.7 mg for Group B (P < 0.001). Findings of mucositis most clearly appeared in the jejunum. Regarding edema (P = 0.003), leukocyte migration (P = 0.038), and inflammation (P = 0.006) significant recovery was detected in the mucosa of rats receiving Saccharomyces boulardii. Villous thickness was significantly greater in Group A than Group B (P < 0.001). The results indicate that Saccharomyces boulardii provided significant improvement in irinotecan-induced diarrhea and mucositis.

Faecal microflora and β-glucuronidase expression are altered in an irinotecan-induced diarrhea model in rats

Objectives: Chemotherapy-induced diarrhea (CID) is a well recognized side effect of cancer treatment. However, the pathophysiology behind this debilitating side effect remains unclear. Irinotecan causes cholinergic and delayed onset diarrhea in patients, in which β-glucuronidase produced by gut bacteria is thought to be involved. Methods: Rats were treated with 200mg/kg irinotecan and killed at various time points up to 72 h. Rats were monitored for diarrhea. Sections were stained for β-glucuronidase expression, and faecal DNA was analysed using real time PCR. Results: Diarrhea occurred, as expected, following irinotecan treatment. β-glucuronidase expression increased in the jejunum and colon. Faecal flora changed quantitatively after treatment also, with increases in E. coli, Staphylococcus spp., and Clostridium spp. (all β-glucuronidase producing), and decreases in Lactobacillus spp., Bifidobacterium spp. (both beneficial bacteria), and Bacteroides spp. (β-glucuronidase producing, major component of intestinal flora). Conclusions: Irinotecan-induced diarrhea may be caused by an increase in β-glucuronidase producing bacteria. However, the increase in bacteria may also be caused by irinotecan, further exaggerating the toxicity of the drug, and emphasising the need for these specific bacteria to be therapeutically targeted for successful treatment regimens to be accomplished.

Activated charcoal to prevent irinotecan‐induced diarrhea in children

We performed a prospective study to evaluate the efficacy of activated charcoal (AC) to prevent irinotecan-induced diarrhea (IID). We designed a prospective trial including all patients receiving irinotecan as part of their chemotherapy treatment. Patients were divided into two groups. The experimental group received AC at a dose of 250 mg three times daily during irinotecan administration. The number and severity of events were graded according to the gastrointestinal toxicity criteria of the NCI Common Toxicity Criteria. We used descriptive statistics, Mann-Whitney U test, and Fisher's exact test to evaluate our results. Twenty-two evaluable patients were included for a total of 66 irinotecan chemotherapy cycles. Ten patients received AC and 12 did not. There were 45 cycles in the experimental group and 21 in the control group. A total of 28 events of diarrhea were registered, 13 in 45 cycles (28.88%) in the experimental group and 15 in 21 cycles (71.42%) in the control group (P = 0.002). Grade 3 and 4 diarrhea was present in 4.4% of patients receiving AC against 52.3% in the controls (P = 0.010). Chemotherapy was discontinued in 6.6% in the experimental group and 52.3% in the control group. The use of AC decreased the frequency and severity of IID improving compliance with treatment. We consider AC and effective and safe prophylactic treatment to prevent IID.

Gentamycin combined with sodium bicarbonate for prevention of irinotecan-induced diarrhea: an analysis of 52 cases

Gentamycin combined with sodium bicarbonate for prevention of irinotecan-induced diarrhea: an analysis of 52 cases

St. John's wort and irinotecan-induced diarrhea

St. John's wort and irinotecan-induced diarrhea

Irinotecan-induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein

Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04-0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49-7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.

Hepatic transport, Metabolism and biliary excretion of irinotecan in a cancer patient with an external bile drain

Background: Irinotecan is metabolized by various enzymes, including carboxylesterases, cytochrome P450 3A isozymes (CYP3A), and uridine-diphosphate glucuronosyltransferase 1A isoforms (UGT1A). Here we report on the disposition of irinotecan and its metabolites in plasma, urine, bile and feces of a single cancer patient with an external bile drain. Methodology: Irinotecan (450 mg) was administered during a 90-minutes continuous infusion to a cancer patient with an external bile drain. Blood samples were collected up to 55 hours after infusion, while bile, feces and urine were collected during 6 consecutive days after administration. Samples were analyzed using high-performance liquid chromatography (HPLC)-assays with fluorescence detection. Results: Plasma pharmacokinetics were characterized by a relatively slow clearance of irinotecan and a relatively high exposure to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC). Exposures to the other metabolites were within the normal range. Overall, 83.4% of the administered dose was recovered in the excreta, with the majority excreted during the first 24 hours. Conclusions: Enterohepatic recirculation is of minor importance for the plasma disposition of irinotecan and its metabolites. The high percentage of the dose recovered in urine, the relatively slow clearance of irinotecan and the preferential urinary over biliary excretion of APC in this particular patient are likely related to reduced functioning of ABC-transporters. Circumstantial evidence was found that APC is subject to further intestinal biotransformation indicating a role in the etiology of irinotecan-induced diarrhea. Since intra-luminal exposure to SN-38 in patients with an external bile drain seems limited, neutropenia will be the dose-limiting toxicity. Based on presented data, although collected from only one patient, irinotecan therapy in patients with an external bile drain is feasible. No a priori dose adjustments are recommended, although depending on the absence of severe side-effects in previous courses, a higher dose may be considered.

St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis

Diarrhea is a common dose-limiting toxicity associated with cancer chemotherapy, in particular for drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. St. John's wort (Hypericum perforatum, SJW) has anti-inflammatory activity, and our preliminary study in the rat and a pilot study in cancer patients found that treatment of SJW alleviated irinotecan-induced diarrhea. In the present study, we investigated whether SJW modulated various pro-inflammatory cytokines including interleukins (IL-1beta, IL-2, IL-6), interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) and intestinal epithelium apoptosis in rats. The rats were treated with irinotecan at 60 mg/kg for 4 days in combination with oral SJW or SJW-free control vehicle at 400 mg/kg for 8 days. Diarrhea, tissue damage, body weight loss, various cytokines including IL-1beta, IL-2, IL-6, IFN-gamma and TNF-alpha and intestinal epithelial apoptosis were monitored over 11 days. Our studies demonstrated that combined SJW markedly reduced CPT-11-induced diarrhea and intestinal lesions. The production of pro-inflammatory cytokines such as IL-1beta, IFN-gamma and TNF-alpha was significantly up-regulated in intestine. In the mean time, combined SJW significantly suppressed the intestinal epithelial apoptosis induced by CPT-11 over days 5-11. In particular, combination of SJW significantly inhibited the expression of TNF-alpha mRNA in the intestine over days 5-11. In conclusion, inhibition of pro-inflammatory cytokines and intestinal epithelium apoptosis partly explained the protective effect of SJW against the intestinal toxicities induced by irinotecan. Further studies are warranted to explore the potential for STW as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities.

Prophylactic treatment of irinotecan-induced diarrhea with neomycin (a randomized, placebo-controlled, double-blind study)

3626 Background: Delayed-type diarrhea is a common side-effect of irinotecan, and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestines. We hypothesized that concomitant administration of the aminoglycoside antibiotic neomycin would diminish exposure of the gut to SN-38, ameliorating the incidence of diarrhea. Methods: Patients were treated with irinotecan in a randomized, placebo-controlled, double-blind trial. In arm A, patients received irinotecan (350 mg/m2 i.v. for 90 minutes once every 3 weeks) combined with neomycin (660 mg orally 3 times daily for 3 consecutive days, starting 2 days before chemotherapy). In arm B, patients received the same irinotecan regimen with placebo. To detect a 50% reduction to less than grade 2 diarrhea (power=.80; P=.05), 60 patients had to be studied. Blood samples for additional pharmacokinetic and pharmacogenetic analyses were obtained after separate informed consent. Results: Sixty-two patients were evaluable for toxicity analysis. Relevant baseline patient characteristics (P&gt;.06), SN-38 plasma concentrations (P=.80; N=43), and UGT1A1*28 genotype status (P=.58; N=52) were similar in both arms. Distribution, severity, and duration of diarrhea did not differ significantly between both arms (P&gt;.32), although grade 3 diarrhea tended to be less frequent in the neomycin arm (45% reduction; P=.19). Grade 2 nausea was more common in this arm (39% vs. 9%; P&lt;.01). The presence of at least one UGT1A1*28 allele was strongly related to the incidence of grade 2–3 diarrhea (69% vs. 34%; P=.01). Conclusions: Our results do not suggest a role for neomycin in the prophylactic treatment of irinotecan-induced diarrhea. In addition, neomycin does not influence systemic SN-38 pharmacokinetics. Also, it is suggested that each patient’s UGT1A1*28 genotype status could be used as a prospective screening tool to prevent severe diarrhea. No significant financial relationships to disclose.

Cefixime Allows Greater Dose Escalation of Oral Irinotecan: A Phase I Study in Pediatric Patients With Refractory Solid Tumors

Irinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea. In separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime. Without cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ng x h/mL; standard deviation [SD], 6.8 ng x h/mL v 10.4 ng x h/mL; SD, 4.3 ng x h/mL, respectively; P = .030). Cefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.

A phase I trial of celecoxib in combination with docetaxel and irinotecan in patients with advanced cancer

This phase I study was conducted to determine the safety, tolerability and maximum tolerated dose of the combination of celecoxib, a selective cyclooxygenase-2 inhibitor, with docetaxel and irinotecan, in patients with advanced solid tumors. Patients with solid tumors received one of three escalating dose levels of daily celecoxib in combination with docetaxel and irinotecan administered on days 1 and 8 of an every 21-day cycle. Toxicities were graded by the National Cancer Institute Common Toxicity Criteria (NCI CTC) and recorded as maximum grade per patient for each treatment cycle. A total of 19 patients received 90 cycles of treatment through three dose levels. Dose-limiting toxicities were nausea and diarrhea. The most common treatment-related toxicities in all cycles of treatment were alopecia, fatigue, diarrhea, nausea, vomiting, anemia, anorexia, and edema.. The maximum tolerated dose was established at celecoxib 400 mg twice a day continuously, weekly docetaxel 30 mg/m2 and irinotecan 50 mg/m2 for 2 weeks every 21 days. Disease stabilization (five or more cycles) was documented in eight patients. The combination of celecoxib with docetaxel and irinotecan did not ameliorate irinotecan-induced diarrhea. Although prolonged disease stabilization was achieved in some patients, we do not recommend combining celecoxib with docetaxel and irinotecan because of lack of activity and the side effect profile of this combination.

Novel Agents that Potentially Inhibit Irinotecan-Induced Diarrhea

Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea.

Phase II Study of Activated Charcoal to Prevent Irinotecan-Induced Diarrhea

The dose-limiting toxicity of irinotecan (CPT-11; Camptosar) is delayed-onset diarrhea, with an incidence at the grade 3 to 4 level of 20% to 35%. SN38, its active moiety, is responsible by a direct effect on mucosal topoisomerase-I. The aim of this study was to assess whether activated charcoal (AC), possibly by adsorbing free lumenal SN38, can reduce irinotecan-induced diarrhea (CID) and optimize its dose-intensity. Patients with advanced colorectal cancer receiving irinotecan 125 mg/m(2) intravenously once a week for 4 weeks every 6 weeks were studied. In cycle 1, patients received irinotecan plus AC (5 mL aqueous Charcodote [1,000 mg AC] plus 25 mL water) given the evening before the irinotecan dose and then tid for 48 hours after the dose. In cycle 2, no AC was given. National Cancer Institute Common Toxicity Criteria diarrhea grade, irinotecan dose-intensity, and loperamide consumption were recorded prospectively in both cycles. Twenty-eight patients had completed cycle 1 with AC; 24 subsequently completed cycle 2 without AC. Grade 3 to 4 diarrhea was 7.1% v 25%, and grade 0 diarrhea was 46.4% v 20.8% in cycles 1 and 2, respectively. Median percent planned dose delivered was 98% v 70% in cycles 1 and 2, respectively. In cycles 1 and 2, respectively, 25% v 54% patients took more than 10 loperamide tablets. AC was well tolerated with excellent compliance. The administration of AC with irinotecan reduced the incidence of grade 3 to 4 diarrhea and antidiarrheal medication consumption and increased irinotecan dose-intensity. Prophylactic AC may have a role in reducing dose-limiting CID and optimizing irinotecan therapy.

Discovery of novel selective inhibitors of human intestinal carboxylesterase for the amelioration of irinotecan-induced diarrhea: synthesis, quantitative structure-activity relationship analysis, and biological activity.

The dose-limiting toxicity of the highly effective anticancer agent 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (irinotecan; CPT-11) is delayed diarrhea. This is thought to be caused by either bacteria-mediated hydrolysis of the glucuronide conjugate of the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) or direct conversion of CPT-11 to SN-38 by carboxylesterases (CE) in the small intestine. After drug administration, a very high level of CPT-11 is present in the bile; this is deposited into the duodenum, the region of the gut with the highest levels of CE activity. Hence, it is likely that direct conversion of the drug to SN-38 is partially responsible for the diarrhea associated with this agent. In an attempt to ameliorate this toxicity, we have applied Target-Related Affinity Profiling to identify novel CE inhibitors that are selective inhibitors of the human intestinal enzyme (hiCE). Seven inhibitors, all sulfonamide derivatives, demonstrated greater than 200-fold selectivity for hiCE compared with the human liver CE hCE1, and none was an inhibitor of human acetylcholinesterase or butyrylcholinesterase. Quantitative structure-activity relationship (QSAR) analysis demonstrated excellent correlations with the predicted versus experimental Ki values (r2 = 0.944) for hiCE. Additionally, design and synthesis of a tetrafluorine-substituted sulfonamide analog, which QSAR indicated would demonstrate improved inhibition of hiCE, validated the computer predictive analyses. These and other phenyl-substituted sulfonamides compounds are regarded as lead compounds for the development of effective, selective CE inhibitors for clinical applications.

Herbal Medicine.

Herbal Medicine.