Scheduling of gemcitabine and cisplatin in Lewis Lung tumour bearing mice

Moorsel, C.J.A. van; Pinedo, H.M.; Veerman, G.; Vermorken, Jan B.; Postmus, Pieter E.; Peters, Godefridus J.

doi:10.1016/s0959-8049(99)00004-0

Cited by 64 publications

(31 citation statements)

References 16 publications

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“…These experiments have clearly confirmed that gemcitabine administration at 11 HALO produced least body weight loss as compared to treatment at 23 HALO, whether gemcitabine was given as a single agent or combined with CDDP. Furthermore, the optimal interval between gemcitabine and CDDP was 4 or 8 h, in accordance with prior reports (van Moorsel et al, 1999b. Our study has thus identified an optimal combination schedule where gemcitabine is given at 11 HALO and CDDP at 15 or 19 HALO, that is, the respective times of least toxicity for each drug alone.…”

Section: Discussionsupporting

confidence: 88%

Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

Tanaka

Sun

et al. 2005

Br J Cancer

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The relevance of gemcitabine timing for chronotherapeutic optimisation was investigated. Healthy mice received multiple doses of gemcitabine (120, 160 or 200 mg kg À1 injection (inj) À1 ) at one of six circadian times (3, 7, 11, 15, 19 or 23 h after light onset -HALO) on days 1, 4, 7 and 10 or a single dose of gemcitabine (400 mg kg À1 ) at 11 or 23 HALO7cisplatin (5 mg kg À1 at 1 min, 4 or 8 h later). Mice bearing Glasgow osteosarcoma received multiple doses of gemcitabine (200 mg kg À1 inj À1 ) at 11 or 23 HALO7cisplatin (5 mg kg À1 inj À1 at 1 min or 4 h later) on days of 10, 13, 16 and 19 following tumour inoculation. A circadian rhythm in body weight loss was statistically validated, with 1030 HALO corresponding to the least toxic time (95% CL, 0800 to 1300). Gemcitabine dosing produced least body weight loss and least neutropenia after injection at 11 vs 23 HALO, whether the drug was given alone or with cisplatin (P ¼ 0.001). Gemcitabine -cisplatin tolerability was improved by dosing gemcitabine at 11 HALO and CDDP at 15 HALO (Po0.001). The administration of this schedule to tumour-bearing mice increased median survival three-fold as compared to treatments where both drugs were given simultaneously at 11 or 23 HALO (P ¼ 0.02). The optimal schedule would correspond to the delivery of gemcitabine upon awakening and cisplatin near mid-activity in cancer patients.

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Section: Discussionsupporting

confidence: 88%

Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

Tanaka

Sun

et al. 2005

Br J Cancer

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“…The maximum tolerated doses of cisplatin in rodents have been reported to range from 6 to 12 mg/kg of body weight, depend- ing on the mouse strain (7,14,30,38). Ten percent lethal dose values of 8 mg/kg (13) to 15.5 mg/kg (37) have been reported for rodents.…”

Section: Resultsmentioning

confidence: 99%

“…Assuming distribution of the drug throughout the body, these doses would produce concentrations of approximately 30 M in animals. Doses used successfully in the treatment of tumors in mice are in the 5-to 10-mg/kg range (13,38), at which antitumor activity relative to toxicity is acceptable. We tested the effects of cisplatin on LT lethality at a range of drug doses (0.125 mg/kg to 10 mg/kg), using a single coadministration of each cisplatin dose with LT (always at 100 g in 1 ml, or 1.1 M).…”

Section: Resultsmentioning

confidence: 99%

Cisplatin Inhibition of Anthrax Lethal Toxin

Moayeri

Wiggins

Lindeman

et al. 2006

Antimicrob Agents Chemother

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Bacillus anthracis lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages derived from certain inbred strains. LT is comprised of a receptor binding component, protective antigen (PA), which delivers the enzymatic component, lethal factor (LF), into cells. We found that mouse macrophages were protected from toxin by the antitumor drug cis-diammineplatinum (II) dichloride (cisplatin). Cisplatin was shown to inhibit LT-mediated cleavage of cellular mitogen-activated protein kinases (MEKs) without inhibiting LF's in vitro proteolytic activity. Cisplatin-treated PA lost 100% of its ability to function in toxicity assays when paired with untreated LF, despite maintaining the ability to bind to cells. Cisplatin-treated PA was unable to form heptameric oligomers required for LF binding and translocation. The drug was shown to modify PA in a reversible noncovalent manner. Not surprisingly, cisplatin also blocked the actions of anthrax edema toxin and of LF-Pseudomonas aeruginosa exotoxin A fusion peptide (FP59), both of which require PA for translocation. Treatment of BALB/cJ mice or Fischer F344 rats with cisplatin at biologically relevant concentrations completely protected the animals from a coadministered lethal dose of LT. However, treatment with cisplatin 2 hours before or after animals received a lethal bolus of toxin did not protect them.

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“…The chemotherapy regimen used in this study was adapted from a 12-day metronomic cisplatin and gemcitabine dosing schedule, shown to have a synergistic effect in the murine Lewis lung carcinoma (LLC) model (van Moorsel et al, 1999). Data suggest that cisplatin might share synergism with gemcitabine, possibly due to the multiple mechanistic interactions of the two drugs; for example, gemcitabine increases tumour Pt retention and Pt-DNA adduct levels (van Moorsel et al, 2000).…”

mentioning

confidence: 99%

Correction of anaemia through the use of darbepoetin alfa improves chemotherapeutic outcome in a murine model of Lewis lung carcinoma

et al. 2005

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Darbepoetin alfa (Aranesp s , Amgen) is a novel erythropoiesis-stimulating protein with a serum half-life longer than recombinant human erythropoietin (Epo), used in the treatment of cancer-associated anaemia. Anaemia is known to adversely affect prognosis and response to treatment in cancer patients. Solid tumours contain regions of hypoxia due to poor vascular supply and cellular compaction. Although hypoxic stress usually results in cell death, hypoxia-resistant tumour cells are genetically unstable and often acquire a drug-resistant phenotype. Increasing tumour oxygenation and perfusion during treatment could have the doubly beneficial outcome of reducing the fraction of treatment-resistant cells, while increasing drug delivery to previously hypoxic tissue. In this study, we examined the effect of darbepoetin alfa on chemotherapy sensitivity and delivery in an in vivo model of Lewis lung carcinoma, shown here to express the Epo receptor (EpoR). We identified that weekly darbepoetin alfa treatment, commencing 10 days before chemotherapy, resulted in a significant reduction in tumour volume compared to chemotherapy alone. This was mediated by the prevention of anaemia, a reduction in tumour hypoxia and a concomitant increase in drug delivery. Darbepoetin alfa treatment alone did not modulate the growth of the EpoR-expressing tumour cells. This study identifies an important role for darbepoetin alfa in increasing the therapeutic index of chemotherapy.

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Scheduling of gemcitabine and cisplatin in Lewis Lung tumour bearing mice

Cited by 64 publications

References 16 publications

Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

Cisplatin Inhibition of Anthrax Lethal Toxin

Correction of anaemia through the use of darbepoetin alfa improves chemotherapeutic outcome in a murine model of Lewis lung carcinoma

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