NATURAL APPROACHES TO ENHANCING CHEMOTHERAPY EFFICACY

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.

NATURAL APPROACHES TO ENHANCING CHEMOTHERAPY EFFICACY

Fish Oil
Caffeine
Theanine

Fish Oil and Chemotherapy
Fish oil may enhance the effectiveness of cancer chemotherapy drugs. A study compared different fatty acids on colon cancer cells to see if they could enhance Mitomycin C, a chemotherapy drug efficacy. Eicosapentaenoic acid (EPA) concentrated from fish oil was shown to sensitize colon cancer cells to Mitomycin C (Tsai et al. 1997). It should be noted that fish oil also suppresses the formation of prostaglandin E2, an inflammatory hormone-like substance involved in cancer cell propagation.

In another study, a group of dogs with lymphoma were randomized to receive either a diet supplemented with arginine and fish oil or just soybean oil. Dogs on the fish oil and arginine diet had a significantly longer disease-free survival time than dogs on the soybean oil (Ogilvie et al. 2000).


Caffeine and Chemotherapy
The use of caffeine in combination with chemotherapy has been shown to enhance the cytotoxicity of chemotherapy drugs. Caffeine occurs naturally in green tea and has been shown to potentiate the anticancer effects of tea polyphenols. In SKH-1 mice at high risk of developing malignant and nonmalignant tumors, oral administration of caffeine (as sole source of drinking fluid for 18-23 weeks) inhibited the formation and decreased the size of both nonmalignant tumors and malignant tumors (Lou et al. 1999).

In cancer, p53 gene mutations are the most common genetic alterations observed, occurring in 50-60% of patients, including those with carcinomas and sarcomas. Caffeine has been shown to potentiate the destruction of p53 defective cells by inhibiting growth in the G2 phase. This ability of caffeine is important because the basis of many anticancer therapies is to damage tumor DNA and destroy the replicating cancer cells. Caffeine uncouples tumor cell-cycle progression by interfering with the replication and repair of DNA (Blasina et al. 1999; Ribeiro et al. 1999; Jiang et al. 2000; Valenzuela et al. 2000).


Theanine and Chemotherapy

Theanine Makes Chemotherapy Work
L-theanine is a unique amino acid, naturally occurring in green tea, shown in one study to enhance Adriamycin concentration in tumors 2.7-fold and reduce tumor weight 62% over controls, whereas Adriamycin by itself did not reduce tumor weight (Sugiyama et al. 1998). Adriamycin is an anthracycline antibiotic having a wide spectrum of antitumor activity. Additionally, L-theanine was shown to reverse tumor resistance to certain chemotherapeutic drugs by forcing more of the drug to stay inside the tumor. It does not, however, increase the amount of drug in normal tissue, which sets it apart from other drugs designed to overcome multidrug resistance (Sadzuka et al. 2000a).


Theanine Makes Chemotherapy Work
In 1999 researchers performed a study testing the use of theanine in conjunction with a drug similar to doxorubicin known as idarubicin. The use of idarubicin has been tried in drug-resistant leukemia cells, but it caused toxic bone marrow suppression.

Researchers wanted to see if theanine would cause the drug idarubicin to work. In the first experiment, about one-fourth of the standard dose of idarubicin was used. At this dose, the drug usually does not work, and it also does not cause toxicity. When combined with theanine, however, idarubicin worked but still without toxicity. Tumor weight was reduced 49%, and the amount of drug in the tumors doubled. In the next experiment, theanine was added to the usual therapeutic dose of idarubicin. Theanine increased the effectiveness of idarubicin and significantly lessened usual bone marrow suppression. Leukocyte loss was reduced from 57% to 37% (Sadzuka et al. 2000c).

Part of theanine's activity can be attributed to its mimicking of glutamate, an amino acid that potentiates glutathione. Theanine crowds out glutamate transport into tumor cells. Cancer cells (in confusion) erringly take in theanine, and theanine-created glutathione results. Glutathione (created by theanine) does not detoxify like natural glutathione, and instead blocks the ability of cancer cells to neutralize cancer-killing agents. Deprived of glutathione, cancer cells cannot remove chemotherapeutic agents, and the cell dies as a result of chemical poisoning (Sadzuka et al. 2001b).