Non-glycanated ΔDCN isoform in muscle invasive bladder cancer mediates cancer stemness and gemcitabine resistance
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Progress in the treatment of pancreatic cancer in the past several decades has been very modest. Several new agents with activity against this disease have been identified. Of these, gemcitabine appears to be the most promising when used in combination with other drugs. Gemcitabine and cisplatin combinations have been tested in several studies. The major toxicity reported to occur with the gemcitabine-cisplatin combination is myelosuppression, which is greater than that encountered with single-agent gemcitabine. However, episodes of neutropenic fever or spontaneous bleeding are reported to be very infrequent. Pilot Phase II studies combining gemcitabine with cisplatin have shown improved outcomes in objective response rates and survival; however, these findings must be confirmed in larger randomized studies. Cancer 2002;95:908–11. © 2002 American Cancer Society. DOI 10.1002/cncr.10757
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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.
Combination therapy
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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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New agents with high anti-tumor effects have been developed since 1990. Monotherapy with one of these agents, gemcitabine, was confirmed to be as effective as the standard chemotherapy regimen against NSCLC, and to have a lower toxicity profile. In addition, the combination of gemcitabine plus cisplatin can be expected to show a survival advantage. The combination therapy consisting of these two new anti-cancer agents is expected to show effectiveness equal to that of platinum-based combination chemotherapy. Gemcitabine is well tolerated, so that it can be a useful treatment for maintaining QOL among the elderly or in poor performance status patients with NSCLC. Considering that this agent is also effective against pancreatic cancer, further investigation for efficacy against other cancers is warranted.
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Combination chemotherapy
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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.
Carboplatin
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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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In this report, we present a new strategy for targeting chemotherapeutics to tumors, based on targeting extracellular DNA. A gemcitabine prodrug was synthesized, termed H-gemcitabine, which is composed of Hoechst conjugated to gemcitabine. H-gemcitabine has low toxicity because it is membrane-impermeable; however, it still has high tumor efficacy because of its ability to target gemcitabine to E-DNA in tumors. We demonstrate here that H-gemcitabine has a wider therapeutic window than free gemcitabine.
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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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