Pre-clinical studies identify novel ways to enhance effect of chemotherapy

November 20, 2002

Frankfurt, Germany: Researchers have found that blocking the action of a growth factor on tumour stroma cells[1] increases the uptake of cancer drugs by the tumour. The findings could be crucial for efforts to make standard chemotherapy work better.

Kristian Pietras, of the Ludwig Institute of Cancer Research in Uppsala, Sweden, has shown in animal studies that inhibiting platelet-derived growth factor (PDGF) signalling increases the tumour uptake of cytotoxic (cell-killing) drugs 2-5-fold. There was no increase seen in the levels of cytotoxic drugs in normal tissue.

Treatment studies with imatinib (GlivecR, Novartis AG), which blocks PDGF signalling, in combination with either of the cytotoxic drugs 5-fluorouracil (5-FU) or paclitaxel, or with the experimental drug, EPO906 (epothilone B), have also been completed. In all cases the combination therapies induced better anti-tumour effects in the animals than the single treatments with chemotherapy alone. The increase in effect occurred without any signs of increased toxicity.

The findings could lead to changes in the way some drugs are used in combination chemotherapy regimens. Studies in patients will be needed to determine whether these novel combinations can improve the lives of patients with some cancers.

"If our findings in animal tests hold up in patients, then we are definitely on to something that could explain why some cancers are more treatable in one type of patients than another and this would be very important. We therefore look forward very much to the results from the patient study that we hope to start around the beginning of next year, " said lead researcher Dr Arne Östman[2].

Dr Östman told a news briefing today (Wednesday 20 November) at the EORTC-NCI-AACR[3] Symposium on Molecular Targets and Cancer Therapeutics in Frankfurt: "There are two types of beneficial effects one can envisage if one could improve drug uptake in tumours - either the same therapeutic effect as now with a reduced dose of drug and reduced side effects, or better therapeutic effects with the maximum tolerated dose."

Dr Östman said that their studies, undertaken together with Professor Kristofer Rubin, Uppsala University, also showed that PDGF receptor signalling in tumour stroma cells plays a role in maintaining a high interstitial fluid pressure (IFP) in tumours. "We believe that the IFP reduction, induced by PDGF antagonists, contributes to the beneficial effect on tumour drug uptake. It's possible that PDGF receptor inhibitors decrease tumour IFP by reducing the contractile force exerted by tumour stroma cells on the surrounding extracellular matrix. However, we will also continue to investigate whether other mechanisms contribute to the beneficial effects of Glivec on tumour drug uptake."

PDGF receptor expression in the tumour stroma, and high IFP, may occur in many types of tumours, including those of the breast, colon and lung, so the findings could have potential application in a range of common cancers.

Dr Östman concluded, "Our study suggests inhibiting PDGF receptor signalling in tumour stroma cells could be a novel method for enhancing the effect of chemotherapy. If future clinical trials based on these experiments show the same results that we have seen in animal models, then we have identified a new and possibly widely applicable strategy for improving drug treatment for cancer patients."

[1] Tumour stroma cells: connective tissue-like cells present in most types of solid tumours

[2] The research team included: Dr Arne Östman (principal investigator, Ludwig Institute), Dr Kristian Pietras (Ludwig Institute), Professor Kristofer Rubin (Uppsala University), Professor Carl-Henrik Heldin (Director, Ludwig Institute), Markus Wartmann and Elisabeth Buchdunger of Novartis Oncology, Switzerland.

[3] EORTC [European Organisation for Research and Treatment of Cancer; NCI [National Cancer Institute]; AACR [American Association for Cancer Research].

Ludwig Institute:
Novartis Oncology:

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European Organisation for Research and Treatment of Cancer

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