<strong>Activity of Vitamin E Phosphate (VEP) Prodrugs of Gemcitabine in a Xenograft Model of NSCLC (NCI-H460)</strong>
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VEP nucleosides bypass two mechanisms of tumor resistance: nucleoside transport and kinase downregulation. Isoforms of VE have shown activity against solid and hematologic tumors. Gemcitabine was conjugated at the 5' position to either δ-tocopherol-MP (NUC050) or δ-tocotrienol-MP (NUC052). NUC050 has been demonstrated to deliver gemcitabine-MP intracellularly. Its half-life IV in mice is 3.9 compared to 0.28 hours for gemcitabine (European J Cancer. 2016. 61(Suppl. 1):S119). When tumors in nude mice reached 32 to 75 mg mm3 (day 4) treatment was initiated with gemcitabine (120 mg/kg IP q3dx9), NUC050 or NUC052 (both 40 mg/kg qwkx4) and compared to saline control (SC). Gemcitabine inhibited tumor growth but was not tolerated. NUC050 resulted in inhibition to tumor growth on days 11-31 (p<0.05), with a nadir of -73% compared to SC. Median survival was 25.5 days (SC) vs 33 days (NUC050) ((hazard ratio) HR=0.24, p=0.017). NUC052 had the dose increased to 50 mg/kg after 2 doses. NUC052 resulted in inhibition to tumor growth on days 14-27 (p<0.05), with a nadir of -45%, and median survival was 34 days (HR=0.27, p=0.033). NUC050 and NUC052 have been shown to be safe and effective in a NSCLC xenograft. Studies have been initiated in a pancreatic cancer xenograft.Background: The Carrier linked prodrug as per literature is known to be a pharmacologically inactive chemical derivative and could be used to change the physicochemical properties of compounds. Codrugs is a type of carrier linked prodrug, and consist of two usually synergistic drugs or moieties attached to each other. Keywords: Prodrugs, codrugs, carrier linked prodrugs, spacer, benorylate.
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A study was conducted to investigate the feasibility and acceptability of administering single-agent gemcitabine to patients with advanced non-small-cell lung cancer (NSCLC) in their own homes. Gemcitabine is an active agent in NSCLC with a good toxicity profile and lends itself to this type of investigation. A total of 24 patients were studied; as only one patient required gemcitabine to be changed from home administration to hospital administration, domiciliary gemcitabine is feasible. A total of 249 injections of gemcitabine were given, the mean number of courses being 3.5, range 1–6. The gemcitabine was given at 1000 mg m−2 on days 1, 8 and 15, the courses being repeated every 28 days. All patients received their first course in hospital and in total 147 were given at home and only 14 in hospital on courses 2–6. Furthermore, both the patients and carers reported positively on the use of domiciliary gemcitabine and preferred it over hospital administration. There was no evidence of increasing burden to community services during the domiciliary chemotherapy. Further studies investigating this approach are warranted.
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Gemcitabine is among the standard first-line agents for the treatment of metastatic pancreatic cancer. However, as the median survival with gemcitabine monotherapy is 6 months, different combinations are being studied for better, prolonged survival. In this multicenter study, we aimed to compare the results of gemcitabine monotherapy with those of gemcitabine and cisplatin combination therapy as first-line treatments for metastatic pancreatic cancer.Data of 664 patients diagnosed with metastatic pancreatic cancer between January 2007 and December 2016 from seven oncology centers in Turkey were retrospectively evaluated, and 319 patients with gemcitabine alone (n=138) or gemcitabine and cisplatin combination (n=181) as first-line treatment were included.The median patient age was 62 years (range 42-79), being 60 years (42-75) in the gemcitabine/cisplatin arm and 67 years (52-79) in gemcitabine alone arm. no complete response was observed in either arm, whereas partial response rates were 30.1% in gemcitabine/cisplatin arm and 15.3% in gemcitabine alone arm (p=0.001). median overall survival was 8 months (95% CI:7.7-10.2) and was significantly longer in the gemcitabine/cisplatin arm than in the gemcitabine alone arm (10 vs. 6 months, p=0.004).The cemcitabine and cisplatin combination therapy as first-line treatment of metastatic pancreatic cancer yields significantly prolonged survival over gemcitabine monotherapy. In patients with favorable performance conditions, the combination therapy should be preferred.
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再発・進行膵癌における化学療法は，gemcitabine 単独療法が標準治療であるが，S-1＋gemcitabine 併用化学療法も第ＩＩ相試験で良好な成績が報告されつつある。今回，S-1＋gemcitabine 併用化学療法が著効し，長期生存中の進行膵癌術後肝転移の1 例を経験したので報告する。症例は59 歳（手術時），女性。膵頭部癌，cT4N0M0，stageＩＶa との診断で術前化学放射線療法（gemcitabine 800 mg/m2＋RT 36 Gy）を施行後，2005 年11 月に膵頭十二指腸切除術を施行した。術後病理組織診断はpoorly differentiated adenocarcinoma，pT4N0M0，StageＩＶa であった。術後外来経過観察中であったが，2006 年10 月，肝S8/7 に径1 cm 大，単発の肝転移を認め，S-1＋gemcitabine 併用化学療法を35 コース施行し（21 days/1 コース，S-180 mg/m2 day 1〜5，8〜12。gemcitabine 1,000 mg/m2 day 6，day 13），CR を得た。本症例においてS-1＋gemcitabine 併用化学療法は，QOL を損なうことなく2 年もの長期の間安全に施行でき，肝転移のcontrol も良好であった。再発膵癌に対する化学療法は，術前にgemcitabine を用いた場合，薬剤耐性を考慮しS-1 との併用療法も有効である可能性が示唆された。
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This randomised phase II trial compared gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer. Patients were randomly assigned to 4-week treatment with gemcitabine alone (1000, mg m−2 gemcitabine by 30-min infusion on days 1, 8, and 15) or gemcitabine and S-1 combination therapy (1000, mg m−2 gemcitabine by 30-min infusion on days 1 and 15 and 40 mg m−2 S-1 orally twice daily on days 1–15). The primary end point was progression-free survival (PFS). Between July 2006 and February 2009, 106 patients were enrolled. The PFS in gemcitabine and S-1 combination arm was significantly longer than in gemcitabine arm (5.4 vs 3.6 months), with a hazard ratio of 0.64 (P=0.036). Overall survival (OS) for gemcitabine and S-1 combination was longer than that for gemcitabine monotherapy (13.5 vs 8.8 months), with a hazard ratio of 0.72 (P=0.104). Overall, grade 3 or 4 adverse events were similar in both arms. Gemcitabine and S-1 combination therapy demonstrated longer PFS in advanced pancreatic cancer. Improved OS duration of 4.7 months was found for gemcitabine and S-1 combination therapy, though this was not statistically significant.
Combination therapy
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Objective To compare the efficacy and toxicity of gemcitabine and gemcitabine plus carboplation in treatment of elderly patients with locally advanced or metastatic non-small-cell lung cancer(NSCLC).Methods 48 eligible patients above 65 years old who had previously been left untreated and were in stageⅢB orⅣNSCLC were randomly assigned to receive either gemcitabine alone(1000 mg/m~2 on days land 8 ) or gemcitabine plus carboplatin(area under the curve 5 on day 1 ) every 21 days. Results The overall response rate was 20.8%in gemcitabine group and 33.3%in gemcitabine with carboplatin group,respectively (P0.05).The median overall survival time was 8.2 months in gemcitabine group and 9.6 months in gemcitabine with carboplatin group(P0.05 ).The 1-year overall survival rate was 32.1%in gemcitabine group and 39.4%in gemcitabine with carboplatin group,respectively(P0.05 ).The frequency of grades 3 to 4 leucopenia and thrombocytopenia was significantly higher in the gemcitabine with carboplatin group(P for both variables0.05 ) but without associated increase in fever,infection or bleeding. Conclusion In advanced NSCLC,the single gemcitabine or gemcitabine plus carboplatin is tolerable and effective for elderly patients with advanced stages ⅢB and Ⅳ NSCLC.
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Purpose Since the combination of cisplatin plus gemcitabine (CG) had a significant survival advantage for the treatment of patients with chemotherapy-naïve advanced or metastatic non-small cell lung cancer (NSCLC), CG combination have been evaluated with different schedules. However, the best schedule is still unclear. We designed to compare the efficacy and toxicity of CG combination chemotherapy in two different doses of gemcitabine (1,000 or 1,250 mg/m2 3-weekly). Materials and Methods We randomized patients with stage III or IV NSCLC into either gemcitabine 1,250 mg/m2 or gemcitabine 1,000 mg/m2. Patients received cisplatin 60 mg/m2 intravenously on day1 of each 3-week cycle. Gemcitabine was administered intravenously on days 1 and 8 of each 3-week cycle. Results From April 2002 until July 2004, 125 patients were enrolled from four university hospitals (55 patients in the gemcitabine 1,000 mg/m2 arm and 70 patients in the gemcitabine 1,250 mg/m2 arm). Response rates were not significantly different in both arms (56.4% vs. 55.7%). However, grade 3 neutropenia was significantly lower in gemcitabine 1,000 mg/m2 arm compared to gemcitabine 1,250 mg/m2 arm (11.0% vs. 15.8%). No differences in non-haematologic toxicities in both arms except anorexia were observed. The median survival was 13.4 months for gemcitabine 1,000 mg group compared with 15.8 months for gemcitabine 1,250 mg group. There were no statistically significant differences in survival between the groups. Conclusion For stage III or IV non-small cell lung cancer, combination chemotherapy with gemcitabine 1,000 mg/m2 showed equivalent response rate with lesser neutropenia and anorexia compared to treatment with gemcitabine 1,250 mg/m2.
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The systemic administration of gemcitabine has been accepted as the first standard treatment for patients with advanced pancreatic cancer. The survival of patients treated by gemcitabine, however, is still unsatisfactory. To improve the anti-tumor effect of gemcitabine, we investigated molecular changes by gemcitabine in in vitro and in vivo pancreatic cancer models. The findings suggested that administering gemcitabine after 5-FU may be the optimal combination of gemcitabine/5-FU treatment for pancreatic cancer. Furthermore, a study with gemcitabine resistant pancreatic cancer cells using both in vitro and clinical models indicated that ribonucleotide reductase M1 subunit would be a key molecule in gemcitabine resistance in human pancreatic cancer and that RRM1 could have potential as a predictor and modulator of gemcitabine treatment.
Ribonucleotide reductase
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