Overcoming resistance

Cancer resistance to chemotherapy is a devastating event. Unfortunately, it is an inevitable one, too.

Dr. Tim Browder, a former lab mate in the Folkman lab, carried out an evocative experiment. He started with a cancer that was chemotherapy-sensitive. The chemotherapy drug would hold the tumor at a certain size for about 30 days, and then after that, it would “escape” and grow super-rapidly in the face of continuing chemotherapy. He kept treating the cancer with the same chemotherapy until it became super-resistant. Eventually the same chemotherapy would only control the tumor size for 13 days, before it “escaped.” In these experiments, the high-dose chemotherapy could be given only once every three weeks because the mouse wouldn’t survive the side effects if it were given more frequently. Then Dr. Browder did something interesting. He lowered the chemotherapy dose to about one-third, and gave it more frequently (every six days). The mouse was able to tolerate receiving the drug so frequently because of the much lower dose. Amazingly, the same drug against the chemotherapy-resistant cancer held the tumor at bay for 50 days (versus 13)! And when it did start growing, it did so very slowly. Furthermore, if he gave a tiny amount of an additional drug that inhibited blood vessels, the tumors disappeared.

How do you explain these observations? Drs. Browder and Folkman believed that a cancer has two compartments: the cancer cell and the endothelial cell (which are an important part of blood vessels). With the infrequent/high-dose schedule, the cancer cells were being targeted, and they eventually became resistant to the drug, and the drug was ineffective. With the frequent/low-dose schedule, the target became the blood vessels that supported the cancer cells. Every living tissue needs blood vessels, cancers included.

You should always ask, hmmm, is the anti-cancer treatment working against the cancer cells, or the non-cancer cells which support the cancer cells? There’s a big difference. Cancer cells are always mutating and easily become resistant to treatments. Non-cancer cells don’t and make an ideal target.

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