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Making Chemotherapy Drugs Work More Effectively

The dose-delivery schedule of chemotherapy drugs can determinate their efficacy in killing cancer cells and the degree of toxicity to the patient. Conventional chemotherapy treatment often uses a maximum tolerated dose (MTD) of chemotherapeutic drugs, typically administered on a schedule that varies from once a week to every 21 days, allowing a period of rest so that healthy tissue has a chance to recover. Unfortunately, while the MTD schedule is convenient for oncologists, allowing them to squeeze more patients each month into their chemotherapy unit, the rest period enables cancer cells to recover and develop survival mechanisms such as new blood vessel growth into the tumor. This means that when the next high dose of chemotherapy is given 7-21 days later, the cancer cells have become more resistant. The administration of the MTD also exposes healthy tissues to more damage.

Some studies indicate that a better approach would be to lower the dose of conventional cytotoxic agents, reschedule their application, and combine chemotherapy drugs with antiangiogenesis agents to effectively interfere with cancer's various growth pathways and inhibit the production of blood vessels (Holland et al. 2000) (http://www.cancer.gov/clinicaltrials/developments/anti-angio-table).

This lower-dose approach, known as metronomic dosing, uses a dosing schedule as often as every day or alternates different chemotherapy drugs every other day instead of administering them all together the same day. An amount as low as 25% of the MTD, sometimes given on alternative days in combination with various signal transduction pathway inhibitors, targets the endothelial cells making up the vessels and microvessels feeding the tumor. Tumor endothelial cells then die with much less chemotherapy than cancer cells and the side effects to healthy tissue and the patient in general are dramatically reduced (Hanahan et al. 2000).

During standard chemotherapy, the typical 21-day rest period is enough to allow the tumor endothelial cells a chance to recover. However, with tighter chemotherapy dose scheduling, the slowly proliferating endothelial cells are unable to recover. In one study, mice were given the chemotherapeutic drug vinblastine at doses far below the MTD. This dose had little effect on tumor growth in the mice. A second group of mice was given the drug DC101 that inhibits the formation of new blood vessels into tumors (by blocking the induction of vascular endothelial growth factor). In the DC101 group of mice, tumor growth was slowed, as it was with the vinblastine, but then tumor growth resumed. However, in a third group of mice, a combination of the two drugs, at the low dose, resulted in full regression of the tumors with no recurrence for 6 months (Klement et al. 2000).

The administration of low doses of conventional chemotherapy drugs on a frequent basis with no breaks enables these drugs to invoke an antiangiogenesis effect, particularly when combined with a tumor endothelial cell-specific antiangiogenic drug (Gately et al. 2001; Man et al. 2002). There are clinical studies using antiangiogenic drugs (http://www.cancer.gov/clinicaltrials/developments/anti-angio-table). As will be described later in this protocol, certain dietary supplements have also been shown to interfere with angiogenesis.

At the time of this writing, a number of animal studies suggested that chemotherapy drugs could work better if the dosing schedule were changed. Human studies are ongoing, meaning it will be difficult to convince an oncologist to incorporate metronomic dosing instead of the standard MTD. While we cannot definitively recommend metronomic (lower dose/more frequent administration) chemotherapy at this time, the results of new human studies on this subject will be posted at www.lefcancer.org.