July 12, 2000 COLUMBUS, Ohio - Researchers at Ohio State University have discovered an entirely new mechanism of drug resistance in cancer cells, and, possibly, a means to overcome the resistance in patients.
The study, published in the July 11 issue of the Proceedings of the National Academy of Science, showed that solid and metastatic tumors produce high levels of substances called growth factors that protect the tumors from the effects of anticancer drugs.
The inability of cancer drugs to destroy metastatic tumors - tumors that have spread from the primary site - is the leading reason why cancer therapy fails.
Clinical trials using the drug suramin to block the growth factors are expected to begin late this summer in certain lung cancer patients.
"Based on what we have seen in animals, we believe that this drug can make a person's tumor more sensitive to traditional chemotherapeutic drugs," said Jessie L-S Au, Distinguished University Professor and Dorothy M. Davis Professor of Cancer Research at Ohio State's Comprehensive Cancer Center.
This, in turn, may improve the effectiveness of chemotherapy and enable doctors to reduce the dosage of chemotherapy needed to treat many patients.
"It would be very exciting if we could make drugs 10 times more effective. We could then improve the usefulness of chemotherapy against cancer. Along the same line, we could use lower doses than are needed now, and a lower dose means lower toxicity to the patient," said Au.
The research team, led by Au, found several years ago that tumors growing under the skin of laboratory rats were far more responsive to chemotherapy than the same tumors growing in the lung and lymph nodes.
Their search for the reason behind this observation led them to the findings reported in the present study. The researchers discovered that high levels of two growth factors -- basic fibroblast growth factor and acidic fibroblast growth factor -- were present in drug-resistant tumors.
Furthermore, they found that while each of these growth factors by themselves had little or no effect on drug resistance, the two in combination increased drug resistance of tumor cells up to 10-fold.
The researchers also found that the growth factors induced resistance to at least three anticancer drugs that have very different chemical structures and very different action mechanisms. This indicates the broad nature of the resistance.
Overall, Au's findings suggest that cancer chemotherapy might be improved by counteracting the action of the two growth factors.
She and her team found that inhibitors of the fibroblast growth factors enhanced the sensitivity of cancer cells to all three anticancer drugs tested.
"Using inhibitors at low, nontoxic levels completely reversed the resistance induced in cancer cells by the fibroblast growth factors," said Au.
Animal studies done by the researchers showed that an inhibitor of fibroblast growth factors, suramin, given at low doses that were sufficient to reverse the resistance but insufficient to have an antitumor effect of its own, could increase the effectiveness of chemotherapy in mice with human lung tumors.
They found that the chemotherapy alone reduced the size of the tumors, but it did not eliminate them. The combination of chemotherapy and suramin, however, completely eliminated the lung tumors in five of 12 mice and shrunk tumors by an additional 10-fold in the remaining animals.
The improved efficacy was achieved without additional toxicity.
"We are hopeful that inhibitors of fibroblast growth factors can make a patient's tumor more sensitive to traditional chemotherapeutic drugs, and plan to test this new therapeutic approach in patients," said Au.
Au and her research team want to next test the use of suramin in patients with non-small cell lung cancer. During the upcoming clinical trials, patients will be given very low doses of suramin to determine if it improves the effectiveness of the standard therapy for the disease.
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