Glivec-chemo combinations warrant study

Pre-clinical studies identify novel ways to enhance chemotherapy

FRANKFURT, Germany — Researchers have found that blocking the action of a growth factor on tumour stroma cells 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 plateletderived growth factor (PDGF) signaling increases the tumour uptake of cytotoxic (cell-killing) drugs two- to five-fold. There was no increase seen in the levels of cytotoxic drugs in normal tissue.

Treatment studies with Glivec (imatinib), which blocks PDGF signaling, 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,” said lead researcher Dr. Arne Östman of the Ludwig Institute.

“We therefore look forward very much to the results from the patient study that we hope to start around the beginning of next year.”

Östman spoke Nov. 20 at a news briefing at the Symposium on Molecular Targets and Cancer Therapeutics in Frankfurt, sponsored by three groups, the European Organisation for Research and Treatment of Cancer, the National Cancer Institute and the American Association for Cancer Research.

“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.”

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.“ 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,” said Östman.