Search

Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data., Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs)., Results: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%)., Conclusions: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib., (© 2018 S. Karger AG, Basel.)

Sulfatinib is a small molecule kinase inhibitor that targets tumor angiogenesis and immune modulation. This phase I study (NCT02133157) investigated the safety, pharmacokinetic characteristics, and preliminary anti-tumor activity of sulfatinib in patients with advanced solid tumors. The study included a dose-escalation phase (50-350 mg/day, 28-day cycle) with a Fibonacci (3+3) design, and a tumor-specific expansion phase investigating the tumor response to treatment. Two sulfatinib formulations were assessed: formulation 1 (5, 25, and 50 mg capsules) and formulation 2 (50 and 200 mg capsules). Seventy-seven Chinese patients received oral sulfatinib; the maximum tolerated dose was not reached. Dose-limiting toxicities included abnormal hepatic function and coagulation tests, and upper gastrointestinal hemorrhage. The most common treatment-related adverse events were proteinuria, hypertension and diarrhea. Among 34 patients receiving sulfatinib formulation 2, one patient with hepatocellular carcinoma and eight with neuroendocrine tumors exhibited a partial response; 15 had stable disease. The objective response rate was 26.5% (9/34) and the disease control rate was 70.6% (24/34). Pharmacokinetic, safety, and efficacy data supported continuous oral administration of sulfatinib at 300 mg as the recommended phase II dose. Sulfatinib exhibited an acceptable safety profile and encouraging antitumor activity in patients with advanced solid tumors, particularly neuroendocrine tumors.

Background: The granisetron transdermal delivery system (GTDS) has been demonstrated effectiveness in the control of chemotherapy-induced nausea and vomiting (CINV) in previous studies. This is the first phase III study to evaluate the efficacy and tolerability of GTDS in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in China., Methods: A total of 313 patients were randomized into the GTDS group (one transdermal granisetron patch, 7 days) or the oral granisetron group (granisetron oral 2 mg/day, ≥2 days). The primary endpoint was the percentage of patients achieving complete control (CC) from chemotherapy initiation until 24 h after final administration (PEEP). Chi-square test and Fisher's exact test were used for statistical analysis., Results: Two hundred eighty-one patients were included in the per protocol analysis. During PEEP, CC was achieved by 67 (47.52%) patients in the GTDS group and 83 (59.29%) patients in the oral granisetron group. There was no statistical significance between the groups (P=0.0559). However, the difference of the CC percentage mainly occurred on the first day of chemotherapy between the groups. The CC was 70.13% on day 1 in the GTDS group, which was significantly lower than that of 91.03% in the oral granisetron group in the full analysis set. In the following days of chemotherapy, the CC was similar between the groups. In terms of cisplatin-contained regimen and female, there was statistical significance between the groups. Both treatments were well tolerated and safe. The most common adverse event was constipation., Conclusions: GTDS provided effective and well-tolerated control of CINV in Chinese patients, especially to non-cisplatin-contained regimen.

Although multidrug resistance (MDR) proteins are known to play a role in drug resistance and modification pharmacodynamic characteristics of certain conventional chemotherapeutics, information about their interactions with tyrosine kinase inhibitors (TKIs) remains fragmentary and somewhat controversial. The chronic administration of TKIs in many clinical situations strongly suggests that any possible interactions with MDR transporters should be studied as a function of time. For example, short periods of exposure to TKIs could provide insights into the nature of the binding to MDR-related proteins, either as substrates or as inhibitors, whereas prolonged exposure to TKIs could provide insights into cellular responses to binding/inhibition of MDR-related proteins. In this report, we provide evidence that suggests that both Gefitinib and Vandetanib may act as transported substrates for Breast Cancer Resistance Protein (BCRP, ABCG2). Conversely, the interaction of Gefitinib and Vandetanib with P-glycoprotein (PgP, MDR1) appeared to be as inhibitors alone. Consistent with this, short periods of exposure (≤24 h) to either Gefitinib or Vandetanib increased the effectiveness of SN-38, the active metabolite of CPT-11. Conversely, prolonged exposure (5 days) decreased SN-38 effectiveness, and was associated with BCRP up-regulation and reduced cell accumulation in S-phase, possibly though reduced intracellular accumulation of SN-38. This report underlines the needs for more detailed characterisation new biologically targeted anticancer drugs, in particular analysing periods of both short and prolonged drug exposure reflecting potentially distinct situations in the clinic in order to optimise future development in combination with established chemotherapeutic approaches.

Objective: To evaluate the safety and efficacy of gefitinib as second-line or even third-line treatment for previously treated patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)., Methods: 156 patients with locally advanced NSCLC which were about to undergo progression after previous chemotherapy were eligible for this study. The regimen was oral intake of gefitinib 250 mg once daily in the morning or afternoon until the disease progression or toxicity has become intolerable. The drug was provided by AstroZeneca Company by its Expanded Access Program., Results: 154 such patients were evaluable for response and toxicity assessment. The overall rate of objective response and disease control was 28.6% (44/154) and 89.6% (138/154). The median duration of response was 7. 5 months. The median time to disease progression (TTP) was 5. 1 months and the median overall survival time (OS) 10.0 months. The actuarial 1-year survival was 41. 0%. The response rate in adenocarcinoma was significantly higher than that in squamous carcinoma (P = 0. 026). The risk of disease progression in patients with squamous carcinoma was 1. 7 times as much as that of adenocarcinoma patients ( P = 0. 011) , and the risk of death in male was 2. 0 times as much as that in female ( P = 0. 002). At least one of these adverse events would be observed in 40.9% (63/154) of these patients, which, however was mild and reversible. Conclusion Gefitinib is effective and safe as a second-line or third-line treatment for previously treated patients with locally advanced or metastatic non-small cell lung cancer.

Background: Basic research of gefitinib (Iressa, ZD1839) has demonstrated the combination effects of gefitinib and chemotherapy were sequence-dependent. To evaluate the efficacy of sequential administration of gefitinib following a minor response or partial response to two to three cycles of chemotherapy, a phase II clinical trial was done in Chinese patients with advanced non-small-cell lung cancer (NSCLC)., Methods: Thirty-three consecutive patients with advanced NSCLC that had been pretreated with at least one chemotherapeutic regimen and were responding to chemotherapy following 2 to 3 cycles of treatment, entered the trial from May 2004 to February 2006. Patients received gefitinib at an oral dose of 250 mg once daily for 4 weeks., Results: Thirty-three patients were evaluable for response and toxicity. The objective response rate was 24.2% (8 of 33) (95% CI, 11% to 42%). The symptom improvement rate was 54.5% (18 of 33) (95% CI, 41% to 69%). The median duration of response was 7 months (95%CI, 4.0 to 13.2 months). The median time to disease progression (TTP) was 6.5 months (95%CI, 0.7 to 16.6 months). The median overall survival time (OS) was 9.8 months (range, 2.1 to 18.0 months), and the actuarial 1-year survival was 36.4%. Toxicity was relatively mild and included only one patient (3.0%) with grade 4 diarrhea, 1 (3.0%) with grade 3 rash, 1 (3.0%) with grade 3 nausea, and 1 with grade 3 vomiting (3.0%)., Conclusion: Preliminary results suggest that sequential administration of gefitinib following a response to chemotherapy may be beneficial for Chinese patients with advanced NSCLC. Further randomized clinical trials are needed.

The combination of the topoisomerase I (Topo I) inhibitor CPT-11 with the anti-epidermal growth factor receptor (EGFR) agent Gefitinib (Iressa, ZD1839) represents a promising medical approach for colorectal cancer patients. In this report, we provide pre-clinical evidences for their optimal combination schedule in HT-29 and LoVo human colon cancer cell lines. We analyzed the different effects that three different combination schedules of SN-38 (the active CPT-11 metabolite) and Gefitinib (Gefitinib before; Gefitinib simultaneously; Gefitinib after SN-38) have on cell growth, cell cycle, apoptosis, and expression/phosphorylation of EGFR, Topo I and some steps of the signal transduction pathway. We first determined the IC(50) of each drug choosing the 5 days exposure for Gefitinib (0.6 and 3.8 microM for LoVo and HT-29 cells, respectively) and 1 day exposure for SN-38 (0.31 and 0.5 microM for LoVo and HT-29 cells, respectively). The different drug combination schedules were tested in various concentrations by using equiactive concentrations of the two drugs. The cytotoxicity of Gefitinib and SN-38 combination was schedule- and concentration-dependent but not cell line-specific. The most synergistic schedule was Gefitinib given after SN-38, with combination indexes (CI) of 0.007 and 0.454 in HT-29 and LoVo, respectively. Analysis of bio-molecular targets showed that Gefitinib was able to modulate SN-38 ability to inhibit Topo I, to accumulate cells in S-phase, and to induce apoptosis. Interestingly, SN-38 was able to activate EGFR and its signal transduction pathway. Confirming preliminary clinical experience of Gefitinib with other cytotoxic drugs, it seems that Gefitinib after SN-38 represents the best cytotoxic combination schedule but the biomolecular basis for this synergism remain to be completely elucidated.

Objective: To investigate the effect of IRESSA (gefitinib, ZD1839) on H22 murine hepatocellular carcinoma., Methods: Mice bearing H22 hepatocellular carcinoma were randomly divided into oral control group, Normal saline (NS) control group, cisplatin (CDDP) d1-5 group, CDDP d6-10 group, IRESSA group, IRESSA combined with CDDP early (IRESSA + CDDP d1-5) group, and IRESSA combined with CDDP lately (IRESSA + CDDP d6-10) group. IRESSA was given by daily gastrogavage for 10 days (day 1-day 10) at 100 mg/kg in body weight (BW). CDDP was given by daily intraperitoneal injection for 5 days (day 1-day 5, or day 6-day 10) at 1.2 mg/kg in BW. The growth inhibiting rate (IR) of tumor, change of BW, spleen index (SI), and amounts of blood leucocyte or hemoglobin were detected., Results: IR of tumor in IRESSA group was not significantly difference with that in CDDP d1-5 group, CDDP d6-10 group, IRESSA + CDDP d1-5 group (P > 0.05). IR of tumor in IRESSA group, CDDP d1-5 group, CDDP d6-10 group, IRESSA and IRESSA + CDDP d1-5 group were 41%, 54%, 46%, and 56%, respectively. IR of tumor in IRESSA + CDDP d6-10 group (26%) was significantly lower than that in CDDP d6-10 group (P < 0.05) or in IRESSA + CDDP d1-5 group (P < 0.01). Compared with oral or NS control groups, SI and net BW in IRESSA group was not significantly difference (P > 0.05). SI and net BW in both IRESSA + CDDP d1-5 group and IRESSA + CDDP d6-10 group were lower markedly than those in IRESSA group (P < 0.01)., Conclusion: Tumor growth of H22 bearing mice was markedly inhibited by IRESSA.

Objective: To compare the efficacy of endocrine therapy with chemotherapy for bone metastasis of breast cancer., Methods: A total of 138 breast cancer patients with bone metastasis, but without visceral metastasis as retrospectively reviewed., Results: The response rates of endocrine therapy and chemotherapy as the first-line therapy were 35.4% and 31.7% (P = 0.687), and the total response rates were 27.1% and 25.0% (P = 0.690). The clinical benefit rates of endocrine therapy and chemotherapy as first-line were 43.9% and 36.6% (P = 0.437), as second-line were 47.8% and 24.2% (P = 0.033), in total treatments were 47.5% and 27.7% (P = 0.001). The median interval to treatment failure (TTF) was 5 months and 2 months (P < 0.001), and that to progression (TTP) was 5 and 2.5 months (P < 0.001) in endocrine therapy and chemotherapy group, respectively., Conclusion: Endocrine therapy is superior to chemotherapy for bone metastasis of breast cancer.

Unlabelled: ZD1839 ("Iressa"), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is currently undergoing preclinical and clinical evaluation in several solid tumors. The present study aimed to assess the effect of ZD1839 in combination with oxaliplatin in the colon cancer cell lines HT-29 and LoVo. For in vitro chemosensitivity testing, cells were treated with serial dilutions of each drug sequentially at a fixed ratio of doses that corresponded to 1/20, 1/10, 1/5, 1/2, 1, 1.5 and 2 times the individual IC(50) values. Oxaliplatin followed by ZD1839 produced a synergistic effect. In contrast, oxaliplatin following ZD1839 exhibited an additive effect at best. Mass spectrometry examination revealed that ZD1839 modestly enhanced cellular oxaliplatin accumulation and platinum-DNA (Pt-DNA) adducts (P>0.05). In additional studies, high-performance liquid chromatography revealed that oxaliplatin had no effect on ZD1839 accumulation. In contrast, ZD1839 markedly inhibited removal of Pt-DNA adducts (P<0.05). With oxaliplatin treatment (1 day) followed by ZD1839 (1 day), then incubation with drug-free medium (1 day), 90% of Pt-DNA adducts remained. Apoptosis examination revealed that oxaliplatin-induced apoptosis was prolonged by sequential oxaliplatin followed by ZD1839 treatment compared with oxaliplatin alone. Further experiments revealed that ZD1839 decreased cellular gamma-glutamyltransferase activity., Conclusions: The above observations provide a mechanistic explanation for the synergy of oxaliplatin followed by ZD1839, and suggest that this treatment combination warrants further preclinical and clinical investigation.

The effect of trastuzumab on patients with HER-2/neu (HER2)-positive gastric cancer has been confirmed in a phase III clinical trial (ToGA study). However, the optimized sequence and synergic mechanism of trastuzumab and chemotherapy are not clear. Our study investigated the effects and mechanisms of trastuzumab in combination with 5-Fluorouracil (5-Fu) or cisplatin (DDP) on gastric cancer cell lines. Flow cytometry was used to determine HER2 expression and cell cycle. MTT assay was performed to evaluate cytotoxicity. Western blotting and RT-PCR were used to analyze signaling transduction and mRNA expression. Sequential 5-Fu followed by trastuzumab and trastuzumab plus DDP followed by trastuzumab produced the best inhibitory effects. Inhibition of HER2-PI3K-AKT signal transduction, downregulation of nucleotide excision repair cross-complementation 1 (ERCC1), and interference with cell cycle distribution may elucidate the synergism between trastuzumab and chemotherapy. These results provide some evidence for designing a rational regime when trastuzumab is being considered to be used in patients with gastric cancer. [ABSTRACT FROM AUTHOR]

Abstract: A new strategy for the enzymatic synthesis of pyrimidine derivatives containing a sugar branch was developed via combining of Michael addition and acylation. The first-step reaction of pyrimidines and vinyl 3-propionyloxy propionate was catalyzed by Amano lipase M from Mucor javanicus in DMSO. The initial reaction rates of different pyrimidines decreased in the order of fluorouracil, uracil, thymine, in agreement with their nucleophilicity. The succeeding regioselective acylation of d-glucose and d-mannose with the Michael adducts was catalyzed by alkaline protease from Bacillus subtilis in pyridine. The d-glucose and d-mannose were all acylated at C-6 position. Moderate yield was obtained for each step. [Copyright &y& Elsevier]