Combined Therapy with Topotecan and Gemcitabine in Patients with Inoperable or Metastatic Non-small Cell Lung Cancer

Dabrow, Michael; Francesco, Michelle; Gilman, Paul; Cantor, Ronald; Rose, Lewis J.; Meyer, Thomas J.

doi:10.1081/cnv-120022363

Cited by 23 publications

(14 citation statements)

References 16 publications

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“…Gemcitabine (2Ј,2Ј-difluorodeoxycytidine) is a nucleoside analogue that shows activity against hematologic malignancies and solid tumors alone (1)(2)(3)(4) or in combination with other chemotherapeutic agents (5)(6)(7). The cellular metabolism of gemcitabine is similar to that of physiologic nucleosides (reviewed in Ref.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line

Jordheim

Cros

Gouy

et al. 2004

Clinical Cancer Research

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Resistance to cytotoxic nucleoside analogues is a major problem in cancer treatment. The cellular mechanisms involved in this phenomenon have been studied for several years, and some factors have been identified. Various strategies to overcome resistance have been suggested, but none has yet shown efficacy in vivo. We developed a gemcitabineresistant cell line (L1210 10K) from the murine leukemic L1210 strain (L1210 wt) by continuous exposure to increasing concentrations of gemcitabine. L1210 10K is highly resistant to gemcitabine (14,833-fold), 1-␤-D-arabinofuranosylcytosine (ara-C; 2,100-fold), troxacitabine (>200-fold), and cladribine (160-fold) and slightly resistant to trimidox (7.22-fold), but does not display cross-resistance to fludarabine or nonnucleoside anticancer drugs. Deoxycytidine kinase mRNA was not detected by quantitative real-time reverse transcription-PCR in L1210 10K cells, whereas expression of thymidine kinase 1 and ribonucleotide reductase subunit R2 gene was moderately reduced. L1210 10K cells also demonstrated in vivo resistance to nucleoside analogues: gemcitabine-or ara-C-treated mice carrying L1210 10K had significantly shorter survival than gemcitabine-or ara-C-treated mice carrying L1210 wt (P < 0.05). UA911, a mononucleotide prodrug (pronucleotide) of ara-C was found to significantly sensitize L1210 10K cells in vitro. These results suggest that reduced deoxycytidine kinase expression is a mechanism of resistance to gemcitabine that is relevant in vivo and can be circumvented by a prodrug approach.

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Section: Introductionmentioning

confidence: 99%

Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line

Jordheim

Cros

Gouy

et al. 2004

Clinical Cancer Research

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“…None of the reported toxicities was cumulative. Topotecan in combination with gemcitabine is currently under investigation in different solid tumors with various schedules [37][38][39][40][41]. Neutropenia and thrombocytopenia were also the DLTs in these studies.…”

Section: Discussionmentioning

confidence: 99%

Dose Finding Study for Combination Treatment with Topotecan and Gemcitabine of Patients with Recurrent Ovarian Cancer after Failure of First-Line Chemotherapy with Paclitaxel and Platinum

et al. 2004

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Objective: Topotecan and gemcitabine have shown mono-activity against different solid tumors including recurrent ovarian cancer after failure of platinum- and paclitaxel-containing therapies. Both drugs affect DNA replication, topotecan additionally inhibits the DNA repair process. Efficacy profiles and different mechanisms of action make the combination of both drugs a promising regimen. Therefore the following dose-finding study was conducted to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of this combination. Based on the monotherapy schedules topotecan was given on day 1–5, and gemcitabine on day 1 + 8 every 21 days. Patients and Methods: Patients with histologically proven ovarian cancer who relapsed after platinum- and paclitaxel-containing therapy were enrolled. 3 different dose levels were investigated. No individual dose escalation or primary use of cytokines were allowed. Results: 23 patients were enrolled, 50% were pretreated with at least 2 platinum-containing therapies; 80 courses were analyzed for toxicity. Thrombocytopenia and leucopenia were the major DLTs. The MTD for phase II trials is 0.50 mg/m² topotecan and 800/600 mg/m² gemcitabine. In this dose level only one therapy-related non-hematological adverse event >grade 2 (grade 3 mycotic stomatitis) and one grade 4 thrombocytopenia occurred. Responses were observed in 6 and stable disease in 4 out of 12 evaluable patients. Median survival was 15.3 (95% CI: 13.2–28.6) months. Conclusion: The results of this phase I study demonstrate the feasibility and tolerability of this new combination in heavily pretreated patients. Based on these results a phase II study was initiated to evaluate the efficacy of this regimen.

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“…Regimens that administer topotecan on a weekly schedule have shown promise in patients with ovarian cancer, NSCLC, and a variety of other solid tumors [14,32,33,35,36]. Early results from a phase II trial suggest that singleagent therapy with weekly topotecan is well tolerated and active in the SCLC setting [18].…”

Section: Discussionmentioning

confidence: 99%

Emerging Role of Weekly Topotecan in Recurrent Small Cell Lung Cancer

Eckardt¹

2004

The Oncologist

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Care and Research, 12855 North Forty Drive, Suite 200, St. Louis, Missouri 63141, USA. Telephone: 314-628-1210; Fax: 314-628-1220; e-mail: jeckardt@tcccr.com Received September 8, 2004; accepted for publication October 9, 2004. ©AlphaMed Press 1083-7159/2004 INTRODUCTIONDespite current attempts at prevention and treatment, lung cancer exerts a heavy toll, causing more than 1 million deaths each year worldwide, which is approximately 18% of

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Combined Therapy with Topotecan and Gemcitabine in Patients with Inoperable or Metastatic Non-small Cell Lung Cancer

Cited by 23 publications

References 16 publications

Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line

Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line

Dose Finding Study for Combination Treatment with Topotecan and Gemcitabine of Patients with Recurrent Ovarian Cancer after Failure of First-Line Chemotherapy with Paclitaxel and Platinum

Emerging Role of Weekly Topotecan in Recurrent Small Cell Lung Cancer

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