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

Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D - Br. J. Cancer (2005)

Bottom Line: Darbepoetin alfa (Aranesp), 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.Solid tumours contain regions of hypoxia due to poor vascular supply and cellular compaction.Darbepoetin alfa treatment alone did not modulate the growth of the EpoR-expressing tumour cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Royal College of Surgeons in Ireland, Education and Research Centre, Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.

ABSTRACT
Darbepoetin alfa (Aranesp), 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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The cytotoxic effects of chemotherapies on tumour cell proliferation. Lewis lung carcinoma cells were cultured in the presence of cisplatin (A) and gemcitabine (B) and viability was assessed after 48 h under aerobic or hypoxic (1% O2) growth conditions using the MTT assay. Data are expressed as a percentage of untreated control cell proliferation under aerobic growth conditions (% means±s.e.m.). Data represent 3 independent 48 h MTT experiments. *P<0.05 vs normoxic control.
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fig7: The cytotoxic effects of chemotherapies on tumour cell proliferation. Lewis lung carcinoma cells were cultured in the presence of cisplatin (A) and gemcitabine (B) and viability was assessed after 48 h under aerobic or hypoxic (1% O2) growth conditions using the MTT assay. Data are expressed as a percentage of untreated control cell proliferation under aerobic growth conditions (% means±s.e.m.). Data represent 3 independent 48 h MTT experiments. *P<0.05 vs normoxic control.

Mentions: The cytotoxic effects of cisplatin (Figure 7A) and gemcitabine (Figure 7B) were assessed in vitro under both aerobic and hypoxic growth conditions to demonstrate the sensitivity of cells to chemotherapy under different environmental conditions. Both cisplatin and gemcitabine reduced tumour cell proliferation to 30–40% of controls under aerobic conditions (P<0.05). Under hypoxic conditions, tumour cell proliferation was reduced; however, the treatment of cells with either chemotherapy had no further effect on hypoxic cells.


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

Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D - Br. J. Cancer (2005)

The cytotoxic effects of chemotherapies on tumour cell proliferation. Lewis lung carcinoma cells were cultured in the presence of cisplatin (A) and gemcitabine (B) and viability was assessed after 48 h under aerobic or hypoxic (1% O2) growth conditions using the MTT assay. Data are expressed as a percentage of untreated control cell proliferation under aerobic growth conditions (% means±s.e.m.). Data represent 3 independent 48 h MTT experiments. *P<0.05 vs normoxic control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361545&req=5

fig7: The cytotoxic effects of chemotherapies on tumour cell proliferation. Lewis lung carcinoma cells were cultured in the presence of cisplatin (A) and gemcitabine (B) and viability was assessed after 48 h under aerobic or hypoxic (1% O2) growth conditions using the MTT assay. Data are expressed as a percentage of untreated control cell proliferation under aerobic growth conditions (% means±s.e.m.). Data represent 3 independent 48 h MTT experiments. *P<0.05 vs normoxic control.
Mentions: The cytotoxic effects of cisplatin (Figure 7A) and gemcitabine (Figure 7B) were assessed in vitro under both aerobic and hypoxic growth conditions to demonstrate the sensitivity of cells to chemotherapy under different environmental conditions. Both cisplatin and gemcitabine reduced tumour cell proliferation to 30–40% of controls under aerobic conditions (P<0.05). Under hypoxic conditions, tumour cell proliferation was reduced; however, the treatment of cells with either chemotherapy had no further effect on hypoxic cells.

Bottom Line: Darbepoetin alfa (Aranesp), 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.Solid tumours contain regions of hypoxia due to poor vascular supply and cellular compaction.Darbepoetin alfa treatment alone did not modulate the growth of the EpoR-expressing tumour cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Royal College of Surgeons in Ireland, Education and Research Centre, Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.

ABSTRACT
Darbepoetin alfa (Aranesp), 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.

Show MeSH
Related in: MedlinePlus