Severe Gastrointestinal Toxicity Research Articles

Mitigation of goblet cell hyperplasia and gastrointestinal toxicity in rats with intermittent combination dosing of PF-03084014 (gamma secretase inhibitor) and dexamethasone.

e13616 Background: Gamma-secretase inhibitors (GSIs), which block activation of the oncogenic protein Notch homolog-1 (NOTCH-1) are associated with severe gastrointestinal toxicity which potentiall...

Phase I/II trial of combined hormonal therapy and hypofractionated accelerated radiotherapy with concomitant intensity-modulated boost for high-risk prostate cancer: Toxicity analysis.

4634 Background: Combined external beam radiotherapy (RT) and 2-3 years of hormonal therapy (HT) is a standard treatment option for high risk localized prostate cancer. Dose escalated RT alone has been shown to improve disease-free survival. Increased sensitivity of prostate cancer to high dose per fraction has led to hypofractionation as a method to radiobiologically escalate dose. We report on the acute and late toxicities of combining hypofractionated RT and HT. Methods: A prospective phase I/II study enrolling patients with any of: clinical T3, PSA ≥20, or Gleason ≥8. Forty-five Gy (1.8 Gy/fraction) was delivered to the pelvic nodes (4-field technique for the first 67 patients and intensity-modulated radiotherapy (IMRT) for the next 30 patients) with a concomitant 22.5 Gy boost to the prostate using IMRT, for a total of 67.5 Gy (2.7 Gy/fraction), in 25 fractions over 5 weeks. Image-guidance was performed using 3 gold seed fiducials. Common Terminology Criteria for Adverse Events v3.0 and Radiation Therapy Oncology Group late morbidity scores were used to assess acute and late toxicities, respectively. Biochemical failure was determined by Phoenix definition. Results: Ninety-seven patients were treated and followed for a median of 39 months, with 88% of patients having a minimum 24 months follow-up. Maximum toxicity scores are reported. Acute gastrointestinal (GI) toxicities were Grade 0 in 7%, 1 in 55%, and 2 in 38%. Acute urinary toxicities were Grade 0 in 3%, 1 in 52%, 2 in 40%, and 3+ in 5%. Late GI toxicities were Grade 0 in 55%, 1 in 39%, and 2 in 6%. There were no Grade 3+ late GI toxicities. Late urinary toxicities were Grade 0 in 81%, 1 in 10%, 2 in 5%, and 3+ in 4%. Most severe (Grade 3+) toxicities resolved at last follow-up with only 1 patient with Grade 3 late urinary toxicity. To date, 3 patients have failed biochemically. Conclusions: Pelvic RT with concomitant hypofractionated IMRT boost to the prostate combined with HT is well tolerated with low rates of severe late GI and urinary toxicity. Additional follow-up is necessary to evaluate biochemical control and 5 year prostate biopsy results. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca, sanofi-aventis

Treatment of Childhood Sarcoma with Irinotecan: Bilirubin Level as a Predictor of Gastrointestinal Toxicity

Irinotecan is a promising anticancer agent for the treatment of childhood cancer un-responsive to conventional chemotherapy. Its active metabolite, 7-ethyl-10 hydroxy-camptothecin (SN-38) is glucuronidated by a uridine-diphosphoglucuronosyl-transferase (UGT1A1) to form an inactive metabolite. It was supposed that patientswith the UGT1A1*28 polymorphism would have a greater prevalence of elevated pre-treatment serum bilirubin levels and higher toxicity. The aim of our study was to investigate the predictive value of pre-treatment bilirubin levels in the development of severe diarrhea in solid tumor patients treated with irinotecan. The survey included14 pediatric patients with refractory sarcomas treated with irinotecan (CPT-11). Patients were grouped based on the development of mild (G0-2) or severe (G3) gastrointestinal toxicity. The simple linear regression model and the non-parametric paired wilcoxon test were adopted for the analysis. P <0.05 was judged to indicate a significant difference. The results showed a significant increase in severity of diarrhea with in creasing total pre-treatment bilirubin. Therefore, we propose that pre-treatmentbilirubin levels can predict gastrointestinal toxicity in pediatric cancer.

Chemotherapy intensity and toxicity among black and white women with advanced and recurrent endometrial cancer

The purpose of this study was to confirm whether black and white women with endometrial cancer are equally tolerant of chemotherapy and identify factors that impact survival. A retrospective review of 169 black women and 982 white women with the International Federation of Gynecologists and Obstetricians stage III, stage IV, or recurrent endometrial carcinoma was performed. All patients received doxorubicin combined with cisplatin. Chemotherapy parameters that were reviewed included relative dose, relative time, and relative dose intensity. Treatment cycles > or =7 were defined as treatment completion. Although black patients were more likely to experience grades 3-4 anemia (20% vs 14%) and genitourinary (5% vs 1%) toxicity, and less likely to experience severe gastrointestinal toxicity (10% vs 17%), the overall incidence of grades 3-4 treatment-related chemotoxicity was the same between the 2 groups (82% vs 82%). There were no differences in the number of cycles received, relative dose (0.57 vs 0.58), relative time (0.77 vs 0.78), or relative dose intensity (0.76 vs 0.76) for black and white patients. Black patients with advanced stage or recurrent endometrial cancer, treated on 4 Gynecologic Oncology Group (GOG) protocols, had similar dose intensity and severe chemotherapy-related toxicity compared with white patients, suggesting that previously described racial disparities in survival among patients in GOG trials may have an novel etiology.

Biological Responses to Arsenic Compounds

Arsenic is a metalloid that generates various biological effects on cells and tissues. Depending on the specific tissue exposed and the time and degree of exposure, diverse responses can be observed. In humans, prolonged and/or high dose exposure to arsenic can have a variety of outcomes, including the development of malignancies, severe gastrointestinal toxicities, diabetes, cardiac arrhythmias, and death. On the other hand, one arsenic derivative, arsenic trioxide (As(2)O(3)), has important antitumor properties. This agent is a potent inducer of antileukemic responses, and it is now approved by the Food and Drug Administration for the treatment of acute promyelocytic leukemia in humans. The promise and therapeutic potential of arsenic and its various derivatives have been exploited for hundreds of years. Remarkably, research focused on the potential use of arsenic compounds in the treatment of human diseases remains highly promising, and it is an area of active investigation. An emerging approach of interest and therapeutic potential involves efforts to target and block cellular pathways activated in a negative feedback manner during treatment of cells with As(2)O(3). Such an approach may ultimately provide the means to selectively enhance the suppressive effects of this agent on malignant cells and render normally resistant tumors sensitive to its antineoplastic properties.

Race does not impact outcome for advanced ovarian cancer patients treated with cisplatin/paclitaxel

The objectives of this study were to confirm whether racial disparity exists with regard to outcome between black women and white women with ovarian cancer and to identify factors associated with the administration of adjuvant treatment that had an impact on survival. A retrospective review of 97 black women and 1392 white women with International Federation of Gynecology and Obstetrics stage III/IV ovarian carcinoma was performed. All patients received paclitaxel combined with cisplatin while participating in 1 of 7 Gynecologic Oncology Group clinical trials. The treatment parameters that were reviewed included relative dose, relative time, and relative dose intensity. The treatment parameters and outcomes were compared between black patients and white patients. There were no differences in relative dose (0.90 vs 0.89), relative time (1.02 vs 0.99), or relative dose intensity (0.90 vs 0.91) received between black patients and white patients. Black women had less grade 3 and 4 leukopenia (53% vs 63%; P<.05) and gastrointestinal toxicity (10% vs 19%; P<.05) than white women. Performance status>0, age>or=70 years, and mucinous histology were associated with not completing treatment (P<.001). The median progression-free survival was 16.2 months for black patients and 16.1 months for white patients, and the median overall survival was 37.9 months and 39.7 months, respectively (P>.05 for all). When they received similar treatment, there was no difference in clinical outcome between black women and white women with advanced stage epithelial ovarian cancer when they received similar treatment as participants in Gynecologic Oncology Group clinical trials. Black patients may experience less severe gastrointestinal toxicity or leukopenia compared with whites when treated with platinum-based chemotherapy.

Oxaliplatin or Irinotecan As Adjuvant Therapy for Colon Cancer: The Results Are In

Oxaliplatin or Irinotecan As Adjuvant Therapy for Colon Cancer: The Results Are In

NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia

Inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSIs) has been proposed as a molecularly targeted therapy in T-cell acute lymphoblastic leukemia (T-ALL). However, GSIs seem to have limited antileukemic activity in human T-ALL and are associated with severe gastrointestinal toxicity resulting from inhibition of NOTCH signaling in the gut. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid sensitivity and co-treatment with glucocorticoids inhibited GSI-induced gut toxicity. Thus, combination therapies with GSIs plus glucocorticoids may offer a new opportunity for the use of anti-NOTCH1 therapies in human T-ALL.

High-dose Extended-Field Irradiation and High-Dose-Rate Brachytherapy With Concurrent Chemotherapy for Cervical Cancer With Positive Para-Aortic Lymph Nodes

To determine the efficacy and toxicity of extended-field radiotherapy (RT) with concurrent platinum-based chemotherapy in patients with uterine cervical carcinoma and positive para-aortic nodes. We retrospectively reviewed the results for 33 women with Stage IB-IVB cervical cancer. Each patient had received 59.4 Gy, including a three-dimensional conformal boost to the para-aortic lymph nodes and 41.4-50.4 Gy of external beam radiotherapy to the pelvis. Each patient also underwent six or seven applications of high-dose-rate brachytherapy (median, 5 Gy to point A at each session). The median follow-up period of surviving patients was 39 months. The most common acute toxicity was hematologic, observed in 23 women. Severe acute and late gastrointestinal toxicity was observed in 3 and 4 patients, respectively. More than three-quarters of patients showed a complete response, encompassing the primary mass, metastatic pelvic, and para-aortic lymph nodes. Of the 33 women, 15 had no evidence of disease, 6 had persistent disease, 4 developed in-field failures, and 6 developed distant failures. The 5-year overall and disease-free survival rate was 47% and 42%, respectively. Concurrent chemoradiotherapy with extended-field radiotherapy is feasible in women with uterine cervical carcinoma and positive para-aortic lymph nodes, with acceptable late morbidity and a high survival rate, although it was accompanied by substantial acute toxicity.

Effect of anti-inflammatory drugs in phosphatidylcholine membranes: A fluorescence and calorimetric study

Abstract NSAIDs are the most prescribed drugs for inflammation, and their use is associated with severe gastrointestinal toxicity. This work focuses on the interaction of NSAIDs with membranes, specifically, on their ability to affect the lipid dynamic properties, since this may explain the compromising effects on the integrity of gastric barrier. Studies covered the assessment of drug–membrane/water partition coefficient and location by derivative spectroscopy and fluorescence quenching techniques and effects on membrane biophysics by DSC. Results indicate that the NSAIDs studied have membrane destabilizing effects, which could be transposed to similar effects in the stomach’s phospholipid layer justifying their toxicity.

T Cell Acute Lymphoblastic Leukemia: NOTCHing the Way toward a Better Treatment Outcome

Gamma-secretase inhibitors block the activation of NOTCH1 but have limited activity against T cell acute lymphoblastic leukemia (T-ALL) and cause severe gastrointestinal toxicity. In a recent study, Real et al. show that a potent gamma-secretase inhibitor potentiates the cytotoxicity of dexamethasone against glucocorticoid-resistant T-ALL cells, while dexamethasone abrogates the gastrointestinal toxicity induced by the gamma-secretase inhibitor.

Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients

To investigate the efficacy and safety of cape-citabine plus irinotecan +/- bevacizumab in advanced or metastatic colorectal cancer patients. Forty six patients with previously untreated, locally-advanced or metastatic colorectal cancer (mCRC) were recruited between 2001-2006 in a prospective open-label phase II trial, in German community-based outpatient clinics. Patients received a standard capecitabine plus irinotecan (CAPIRI) or CAPIRI plus bevacizumab (CAPIRI-BEV) regimen every 3 wk. Dose reductions were mandatory from the first cycle in cases of > grade 2 toxicity. The treatment choice of bevacizumab was at the discretion of the physician. The primary endpoints were response and toxicity and secondary endpoints included progression-free survival and overall survival. In the CAPIRI group vs the CAPRI-Bev group there were more female than male patients (47% vs 24%), and more patients had colon as the primary tumor site (58.8% vs 48.2%) with fewer patients having sigmoid colon as primary tumor site (5.9% vs 20.7%). Grade 3/4 toxicity was higher with CAPIRI than CAPIRI-Bev: 82% vs 58.6%. Partial response rates were 29.4% and 34.5%, and tumor control rates were 70.6% and 75.9%, respectively. No complete responses were observed. The median progression-free survival was 11.4 mo and 12.8 mo for CAPIRI and CAPIRI-Bev, respectively. The median overall survival for CAPIRI was 15 mo (458 d) and for CAPIRI-Bev 24 mo (733 d). These differences were not statistically different. In the CAPIRI-Bev, group, two patients underwent a full secondary tumor resection after treatment, whereas in the CAPIRI group no cases underwent this procedure. Both regimens were well tolerated and offered effective tumor growth control in this outpatient setting. Severe gastrointestinal toxicities and thromboembolic events were rare and if observed were never fatal.

γ-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia

SummaryGamma-secretase inhibitors (GSIs) block the activation of oncogenic NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of Klf4, a negative regulator of cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of Ccnd2 and protected mice from developing intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.

A phase I study of tipifarnib combined with conventional induction and consolidation therapy for previously untreated patients with acute myeloid leukemia aged 60 years and over

Patients aged 60 years and over with previously untreated acute myeloid leukemia were enrolled in a Phase I study combining tipifarnib with standard induction therapy. The regimen consisted of cytarabine 100 mg/m(2)/day continuous intravenous (i.v.) infusion on days 1-7, daunorubicin 60 mg/m(2)/day i.v. push x 3 on days 6-8 and tipifarnib twice daily on days 6-15. Tipifarnib was escalated over four dose levels (200, 300, 400 and 600 mg). Patients achieving complete response (CR) were eligible to receive one consolidation using the same regimen. The following dose-limiting toxicities (DLTs) were identified during induction: dose level I: 2/6 (hyperbilirubinemia, respiratory arrest), level II: 0/3, level III: 0/3 and level IV: 4/10 (one each of diarrhea, neutropenic enterocolitis, arrhythmia and delayed hematologic recovery post-consolidation). There were no DLTs due to delayed hematologic recovery post-induction. Of 22 evaluable patients, there were 10 CR, 2 morphologic leukemia-free state (MLFS), 2 partial remission (PR) and 8 non-responders. Of seven patients with adverse risk cytogenetics, there were four CR/MLFS and one PR. In summary, this regimen was well tolerated and the maximum tolerated dose was not reached, although somewhat more severe gastrointestinal toxicity was seen at dose level IV. Tipifarnib 600 mg b.i.d. is considered the recommended dose for further study using this regimen.

Diflomotecan, a promising homocamptothecin for cancer therapy

Diflomotecan, a 10,11-difluoro-homocamptothecin, represents a new promising class of topoisomerase I inhibitors with enhanced plasma stability and superior preclinical anti-tumour activity as compared to the established camptothecins, irinotecan and topotecan. Diflomotecan was the first homocamptothecin to enter clinical studies. Phase I data are summarized for both the intravenous and oral schedules. The toxicity is primarily haematological while no severe gastrointestinal toxicity has been observed in contrast to other topoisomerase I inhibitors. Diflomotecan has a high oral bioavailability (72 – 95%) and the oral day 1 – 5 every 3 weeks regimen is recommended for Phase II testing because it is relatively well tolerated, convenient and mimics protracted exposure. This review summarizes the developments and innovations in the topoisomerase I inhibitor field with an emphasis on diflomotecan.

Melphalan 200 Mg/m2 (Mel200) Versus Melphalan 100 Mg/m2 (Mel100) in Newly Diagnosed Myeloma Patients: A Prospective, Randomized Phase III Study

Background. Several trials have shown the superiority of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100.Aims. The primary end points were complete remission (CR) rate, event-free survival (EFS) and incidence of gastrointestinal toxicity, infections and treatment-related mortality (TRM).Methods. Inclusion criteria were previously untreated myeloma, aged ≤ 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal pulmonar, cardiac, liver and renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received 2 cycles of 28-day-dexamethasone- doxorubicin-vincristine (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1–4) and 2 cycles of cyclophosphamide (4 g/m2, day 1) followed by stem cell harvest. MEL200 patients was conditioned with 2 cycles of melphalan 200 mg/m2 and MEL100 patients with 2 courses of melphalan 100 mg/m2. All MEL courses were followed by stem cell reinfusion.Results. Two-hundred and ninety-eight patients (median age 57) were randomly assigned either to MEL200 (149 patients) or to MEL100 (149 patients). All patients were evaluated for response, EFS and OS in intention-to-treat analysis. Patient characteristics were similar in both groups with the exception of chromosomal 13 deletion, present in 69% of MEL200 and 45% of MEL100 patients (p=0.02). Ninety-six patients completed tandem MEL200; 103 tandem MEL100. The very good partial response rate was higher in MEL200 group (37% versus 21%, p=0.003), but CR was 15% in the MEL200 group and 8% in the MEL100 group (p=0.07). The median follow-up for censored patients was 40.5 months. The 4-years EFS was 44.5% in the MEL200 and 18.3% in the MEL100 group (HR=0.71, 95% CI 0.53–0.95, p=0.02). The 5-years overall survival (OS) was 59.2% in the MEL200 and 44.7% in the MEL100 group (HR=0.78, 95% CI 0.52–1.16, p=0.22). Duration of grade 4 neutropenia and thrombocytopenia was comparable, but a higher proportion of MEL200 patients required platelet transfusions (p=0.002). Grade 3–4 non-hematologic adverse events were reported in 38% of MEL200 patients and in 19% of MEL100 patients (p<0.0001). The incidence of grade 3–4 mucositis was 16% after MEL200 and 3% after MEL100 (p<0.0001). The incidence of severe gastrointestinal toxicity was 19% after MEL200 and 2% after MEL100 (p<0.0001). The incidence of grade 3–4 infections and of TRM was similar in both groups.Conclusions. In conclusion, MEL200 resulted in a significantly higher very good partial response rate. This translated in a superior EFS, but not OS. Mel200 was associated with less gastrointestinal toxicity, including mucositis.

Inhibition of NOTCH1 Signaling and Glucocorticoid Therapy in T-ALL

Activating mutations in NOTCH1 are present in over 50% of T-cell acute lymphoblastic leukemias (T-ALL). Consequently, inhibition of NOTCH1 signaling with small molecule γ-secretase inhibitors (GSIs) has been proposed as a targeted therapy for this disease. However, GSIs fail to induce robust apoptosis in T-ALL cells and their clinical application has been limited by the development of severe gastrointestinal toxicity (mucous diarrhea and goblet cell metaplasia) resulting from systemic inhibition of NOTCH signaling. Here we show that combination therapy with GSIs plus glucocorticoids can reverse both glucocorticoid resistance in T-ALL and the occurrence of GSI-induced gut toxicity in vivo. The development of glucocorticoid resistance in T-ALL has been associated with the loss of a positive auto-regulatory transcriptional feedback loop required for glucocorticoid induced apoptosis. Using gene expression profiling and ChIP-on-chip analysis we demonstrated that HES1, a transcriptional repressor controlled by NOTCH1, inhibits specific regulatory elements in the glucocorticoid receptor promoter required for effective glucocorticoid receptor autoupregulation and glucocorticoid induced cell death. Consequently, downregulation of HES1 via inhibition of NOTCH1 signaling with GSIs or HES1 inactivation via shRNA knockdown restores glucocorticoid receptor autoupregulation and reverses glucocorticoid resistance in T-ALL cell lines and primary patient samples. Consistent with these results, combination therapy with dexamethasone and GSIs was highly effective in a mouse xenograft model of glucocorticoid resistant T-ALL. Surprisingly, these studies demonstrated not only improved antileukemic responses in mice treated with dexamethasone plus a GSI compared with dexamethasone or placebo treated controls (P<0.05), but also decreased mortality associated with GSI-induced gut toxicity in this model (P<0.01). These results suggested that glucocorticoids may have an enteroprotective effect against GSI-induced gut toxicity. Detailed histological analysis demonstrated a block of proliferation and increased goblet cell numbers in the intestine of GSI treated animals and a moderate increase in proliferation accompanied by increased Paneth cell numbers in the dexamethasone treated group. Notably, cotreatment with dexamethasone plus a GSI completely reversed the induction of goblet cell metaplasia typically induced by systemic inhibition of NOTCH signaling with GSIs. Likewise, dexamethasone also protected RBPJ-K conditional knockout mice, a genetic model of loss of NOTCH signaling, from developing goblet cell metaplasia in the gut. Interestingly, gene expression profiling analysis showed a marked upregulation of cyclin D2 expression in the gut of glucocorticoid treated mice. Moreover, dexamethasone treatment failed to protect Ccnd2 knockout animals from developing GSI-induced metaplasia, demonstrating a critical role of Ccnd2 upregulation in the protective effects of dexamethasone against GSI-induced gut toxicity. Overall, these results uncover a NOTCH1-HES1-glucocorticoid receptor regulatory axis in glucocorticoid resistant T-ALL and demonstrate an unanticipated protective effect of glucocorticoids against GSI-induced gut toxicity. Our studies warrant the clinical testing of glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.

Pharmacokinetic-directed dosing of vandetanib and docetaxel in a mouse model of human squamous cell carcinoma.

Docetaxel, usually administered according to maximum tolerated dose (MTD), can inhibit endothelial cell proliferation at low nanomolar concentrations. Docetaxel may exert antiangiogenic effects if dosed so plasma levels are maintained at low nanomolar concentrations over a prolonged time. We evaluated metronomic and MTD-based dosing of docetaxel with and without vandetanib, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity, in a head and neck xenograft model. A murine physiologically based pharmacokinetic model was modified to predict docetaxel distribution following i.p. administration to design dosing regimens that target prespecified plasma concentrations, for antiendothelial effects (metronomic), or exposure, to mimic 30 mg/m2 (weekly/MTD) docetaxel in humans. Animals were treated for 28 days with 1 mg/kg/d (DTX1) or 6 mg/kg q4d (DTX6) docetaxel with or without vandetanib (15 mg/kg/d p.o.) in mice bearing UMSCC2 tumor xenografts. The DTX1 dosing scheme was adjusted to treatment for 10 days followed by 9 days off due to severe gastrointestinal toxicity. All treatment groups significantly reduced tumor volume, tumor proliferation (Ki-67), and tumor endothelial cell proliferation (Ki-67/von Willebrand factor) compared with control. Addition of vandetanib to docetaxel treatment significantly enhanced tumor growth inhibition over single-agent therapy. A positive correlation of tumor endothelial cell proliferation with tumor growth rates demonstrates vandetanib and docetaxel antiangiogenic effects. Due to the morbidity observed with DTX1 treatment, it is difficult to clearly ascertain if metronomic schedules will be effective for treatment. Docetaxel with vandetanib is effective in treating UMSCC2 xenografts at concentrations relevant to exposures in humans.

α-CTLA-4 mAb-associated Panenteritis

Monoclonal antibodies (mAbs) against the cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule are used as an adjuvant to experimental tumor immunization protocols in the treatment of malignant melanomas and ovarian cancers. Aside from noted early therapeutic successes, a spectrum of adverse effects, including severe gastroenteritis, has been reported. We report herein our observations of 5 patients who developed severe gastrointestinal toxicity affecting the gastric, small intestinal, and colonic mucosa. The endoscopic findings were variable, ranging from normal to diffusely erythematous and ulcerated mucosa. The constant histologic findings included a lymphoplasmacytic expansion of the lamina propria with increase in intraepithelial lymphocytes. Increased epithelial apoptosis was also a distinctive feature. Cryptitis and glandular inflammation were observed in the colon, ileum, and stomach, whereas villous blunting was present in the ileal and duodenal mucosa. Immunohistochemical analysis revealed a marked increase of all T-cell subsets (CD3+, CD4+, and CD8+) and of CD4CD25 regulatory T cells. We conclude that the panenteritis associated with injection of alpha-CTLA-4 mAbs demonstrates histology resembling autoimmune enteropathy. Furthermore, although the pathogenesis of immune dysregulation after the infusion of alpha-CTLA-4 mAbs remains unclear, we suspect that the increased number of regulatory T cells in the gastrointestinal mucosa may play a role in the pathogenicity.

Action of ( R)-sila-venlafaxine and reboxetine to antagonize cisplatin-induced acute and delayed emesis in the ferret

The chemotherapeutic drug cisplatin is associated with severe gastrointestinal toxicity that can last for several days. A recent strategy to treat the nausea and emesis includes the combination of a 5-HT 3 receptor antagonist, a glucocorticoid, and an NK 1 receptor antagonist. The present studies explore the use of the selective noradrenaline reuptake inhibitors, ( R)-sila-venlafaxine, ( R, R)-reboxetine and ( S, S)-reboxetine to prevent cisplatin (5 mg/kg, i.p.)-induced acute (0–24 h) and delayed (24–72 h) emesis in ferrets. The positive control regimen of ondansetron and dexamethasone, both at 1 mg/kg/8 h, reduced acute and delayed emesis by 100 ( P < 0.001) and 61% ( P < 0.05). ( R)-sila-venlafaxine at 5 and 15 mg/kg/4 h reduced acute emesis by 86 ( P < 0.01) and 66% ( P < 0.05), respectively and both enantiomers of reboxetine at 1 mg/kg/12 h also reduced the response by ∼ 70–90% ( P < 0.05). Out of the reuptake inhibitors, only ( R)-sila-venlafaxine at 15 mg/kg/4 h was active to reduce delayed emesis (a 57% reduction was observed ( P < 0.05)); its terminal plasma levels were positively correlated with an inhibition of emesis during the delayed phase ( P < 0.05). ( R)-sila-venlafaxine was also examined against a higher dose of cisplatin 10 mg/kg, i.p. (3 h test) and it dose-dependently antagonized the response (maximum reduction was 94% at 10 mg/kg, p.o.; P < 0.01) but it was ineffective against apomorphine (0.125 mg/kg, s.c.) and ipecacuanha (2 mg/kg, p.o.)-induced emesis ( P > 0.05). In conclusion, the studies provide the first evidence for an anti-emetic potential of noradrenaline reuptake inhibitors to reduce chemotherapy-induced acute and delayed emesis.