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Cancer researchers have recognized that angiogenesis – the growth of new blood vessels – is needed to support tumor growth. A strategy for stopping cancer is to give the patient drugs that stop angiogenesis. A number of angiogenesis inhibitors or anti-angiogenesis drugs were developed and investigated in the 1990s and 2000s. Some of them did well enough to garner regulatory approval. However, the excitement that researchers had for anti-angiogenesis drugs in the 1990s had faded as the new agents have not turned out to be miracle drugs.
Resistance to anti-angiogenic drugs has turned out to be a problem, and the drugs only extend survival a few months on average. When scientists studied animals on VEGF-targeted angiogenesis inhibitors, it turned out the drugs actually may have promoted metastasis of the cancer even as they thwarted the growth of the main tumor.
But other researchers noticed that traditional cytotoxic chemotherapy medicines, not the special targeted therapy ones, also had some anti-angiogenic activity when administered at low levels. Because blood vessels are lined by genetically stable endothelial cells, they do not evolve resistance, and chemotherapy can be antiangiogenic. This led to the concept of metronomic chemotherapy: giving patients chemotherapeutic agents over the long term at relatively low doses, and with no drug-free breaks. The doses are low enough that side effects are not a major problem.
The metronomic chemotherapy philosophy stands in contradiction to traditional chemotherapy regimens, which called for higher doses often limited largely by the body’s capacity to handle the side effects, and for limited campaigns of several weeks in order to avoid drug resistance and avoid too much harm to the body’s organs. Metronomic chemotherapy uses the conventional cytotoxic drugs but counts on them to stop or slow blood vessel growth. The name metronomic comes from the idea of regular administration of the drug.
Figuring out metronomic chemotherapy regimens
Doctors and scientists tried to work out the best methods and applications through clinical investigation, and trials of different metronomic chemotherapy regimens. Multiple myeloma, ovarian cancer, prostate cancer, and breast cancer, were treated with metronomic chemotherapy with some success in clinical trials. It was not a miracle cure – there are no miracle cures in cancer – but the investigators concluded the approach could be useful.
Other clinical trials did not show benefit from metronomic chemotherapy. Glioblastoma and renal-cell carcinoma were among the cancers for which metronomic chemotherapy was not effective in clinical trials.
Some regimens combined a metronomic administration of cytotoxic drugs plus an explicit angiogenesis inhibitor such as Avastin (bevacizumab). There are side effects – the same as for traditional administration regimens – but they are generally tolerable.
Cytotoxic drugs such as cyclophosphamide and taxane were known to have anti-angiogenic activity and the metronomic schedule appears to enhance this.
Does it work on the endothelial cells that give rise to blood vessels by stopping the proliferation or causing them to die? Or by stopping the movement of the endothelial cells into place to create new vessels? Scientists aren’t sure in all cases, and it may be different from chemotherapy agent to agent.
The cancer is thought to be stopped, in anti-angiogenesis therapy, by starving the tumor. Without new blood vessels the tumor cannot get enough nutrients to grow. Metronomic administration of drugs may trigger another mechanism – namely by making the body’s immune system more sensitive to the cancer. While such drugs as the anthracyclines and taxanes suppress part of the immune system – fewer white blood cells, for instance – they may actually help the immune system become stronger by increasing the numbers of some types of T-cells as well as tumor-unspecific effector cells (natural killer [NK] and NK T cells.)
Other scientists have found that in mouse studies low levels of cytotoxic agents may induce the maturation of dendritic cells in the immune system and thereby call the immune system to action, so to speak. It is sometimes speculated that cancers have a way to “hide” from the immune system, and this method seems to enhance the ability of the immune system to find tumors.
Some mouse studies have found that, in animals with deficient immune systems, metronomic chemotherapy worked for a while and then stopped working. This might be because the cancer cells that can survive with low levels of nutrients survived and multiplied – essentially the cancer evolved in response to the drug.
Another strategy cancer researchers are looking into is to cause the cancer to go dormant. This means the body still has cancer cells in it, but the cancer is not growing or a threat to overall health. It has been known since the 1970s that tumors without blood vessels can be dormant. There are suggestions that metronomic chemotherapy can help induce tumor dormancy, although this hasn’t been proven.
Another way that metronomic chemotherapy might work is by forcing an evolution/dependency in the tumor and then taking away the chemotherapy. The sudden removal will kill the cancer.
Animal and in vitro tests have suggested this might be a path for defeating the cancer.
How feasible would it be to give patients metronomic chemotherapy? Intravenous administration might pose a problem because the patient would have to be hooked up every day or two. But the oncology world is used to working with ports in the body, so that might work. Oral chemotherapy drugs would be easier to work with. It has been proposed that the oral drugs cyclophosphamide and methotrexate be used for breast cancer cases.