~Cancer Chemotherapy, Part 2 - Increasing the Effectiveness of Chemotherapy

Inhibiting the COX-2 Enzyme

Some progressive oncologists are prescribing cyclooxygenase-2 (COX-2) inhibitor drugs along with chemotherapy to improve the odds of successful treatment. COX-2 is an enzyme that many types of cancers use in order to propagate. COX-2 and its byproducts such as prostaglandin E2 (PGE2) have been shown to help fuel the growth of cancers such as colon, pancreas, estrogen-negative breast, prostate, bladder, and lung, to name just a few.

Drugs that inhibit the cyclooxygenase enzyme are known as COX-2 inhibitors. Celebrex and Vioxx are two popular COX-2 inhibitors. Both Celebrex and Vioxx are nonsteroidal anti-inflammatory drugs (NSAIDs) that are usually prescribed to treat the symptoms of rheumatoid arthritis and osteoarthritis. There appears to be more research about Celebrex in the treatment of cancer than Vioxx. There are also other COX-2 inhibiting drugs and nutrients.

Since chemotherapy can cause gastrointestinal bleeding, careful physician monitoring is needed when using a COX-2 inhibiting drug such as Celebrex. Caution is urged for those with known kidney disease, poor heart-lung function, liver disease, or susceptibility to stress-induced ulcers. Cancer Treatment: The Critical Factors has a detailed description of the connection between COX-2 and cancer and why inhibiting the COX-2 enzyme is so important in treating many cancers.

In 1996, Life Extension recommended that most cancer patients take a COX-2 inhibiting drug because of solid evidence that cancer cells use the COX-2 enzyme as a biological fuel to sustain their rapid division. In 1996, Americans had to import a COX-2 inhibitor named nimesulid from other countries because this class of drug was not widely available in the United States.

What has scientists so excited about COX-2 inhibiting drugs are experiments in laboratory animals that suggest that drugs such as Celebrex could help cure cancer, especially if combined with chemotherapy or radiation (Hsueh et al. 1999; Pyo et al. 2001; Swamy et al. 2002). One scientist estimates there are 100 separate cancer studies involving COX-2 inhibitors going on worldwide at this time.

According to an Associated Press news release on March 30, 2002, doctors are predicting that COX-2 inhibiting drugs may become standard therapy in 5-10 years. There was adequate evidence in 1996, however, to recommend COX-2 inhibiting drugs to cancer patients. There are three potent COX-2 inhibiting drugs on the American marketplace. You may ask your physician to prescribe one of the following COX-2 inhibitors:

  • Lodine XL, 1000 mg once a day or
  • Celebrex, 200-400 mg every 12 hours or
  • Vioxx, 12.5-25 mg once a day


Controlling Cancer Cell Growth

A family of proteins known as Ras oncogenes often governs the regulation of cancer cell growth. The Ras family is responsible for modulating the regulatory signals that direct the cancer cell cycle and rate of proliferation. Mutations in genes encoding Ras proteins have been intimately associated with unregulated cell proliferation, that is, cancer.

There is a class of cholesterol-lowering drugs known as statins that has been shown to inhibit the activity of Ras oncogenes. Some of these cholesterol-lowering drugs are lovastatin, simvatatin, and pravastatin (Ura et al. 1994; Narisawa et al. 1996; Tatsuta et al. 1998; Wang et al. 2000; Furst et al. 2002; van de Donk et al. 2002).

In advanced primary liver cancer (hepatoma or hepatocellular carcinoma), patients who received 40 mg of pravastatin survived twice as long compared to those who did not receive this statin drug (Kawata et al. 2001). Interestingly, statins are also associated with the preservation of bone structure and improvement in bone density (Edwards et al. 2000; 2001; Pasco et al. 2002).

Some types of cancer (breast and prostate) have a proclivity to metastasize to the bone (Waltregny et al. 2000; Pavlakis et al. 2002). The result may be bone pain that also may be associated with weakening of the bone and an increased risk of fractures (Papapoulos et al. 2000; Plunkett et al. 2000). Patients with prostate cancer, for example, are found to have a very high incidence of osteoporosis even before the use of therapies that lower the male hormone testosterone (Berruti et al. 2001; Smith et al. 2001).

In settings such as prostate cancer, when excessive bone loss is occurring, there is a release of bone-derived growth factors, for example, TGF-b1 (transforming growth factor-beta 1), that stimulate the prostate cancer cells to grow further (Reyes-Moreno et al. 1998; Shariat et al. 2001). In turn, prostate cancer cells elaborate substances such as interleukin-6 (IL-6) that facilitates the further breakdown of bone (Paule 2001; Garcia-Moreno et al. 2002). Thus, a vicious cycle results: bone breakdown-stimulation of prostate cancer cell growth that results in production of IL-6 and other cell products, which leads to further bone breakdown. When there is a breakdown of bone, the growth factors released can fuel cancer cell growth. (All cancer patients should refer to the Osteoporosis protocol in order to optimally maintain bone integrity and prevent the release of these cancer cell growth factors. The Prostate Cancer protocol has an extensive discussion about the importance of maintaining bone integrity.)

As far as statin drug dosing, higher amounts than required to lower cholesterol are suggested for a multimonth period. Cancer patients, for instance, have used 80 mg a day of lovastatin (Mevacor). This should be considered especially during chemotherapy in some cancers. A monthly SMAC/CBC blood test is also recommended while taking a statin drug to monitor liver function. A rare potential side effect that can occur with the use of statin drugs is a condition known as rhabdomyolysis in which muscle cells are destroyed and released into the bloodstream. If muscle weakness should occur, alert your doctor so you can have a creatine kinase (CK) test to determine if muscle damage has occurred.

Combining a COX-2 Inhibitor with a Statin Drug and Chemotherapy

Depending on the type of cancer, a logical approach would be to combine a statin (such as Mevacor) with a COX-2 inhibitor and the appropriate dosing of chemotherapy.

A study in the journal Gastroenterology showed Mevacor augmented up to fivefold the cancer-killing effect of the COX-2 inhibitor Sulindac (Agarwal et al. 1999). In this study, three different colon cancer cell lines were induced to undergo apoptosis by depriving them of COX-2. When Mevacor was added to the COX-2 inhibitor, the kill rate increased fivefold.

Physician involvement is essential to mitigate potential side effects of these drugs. Those who are concerned about potential toxicity should take into account the fact that the types of cancers that these drugs might be effective against have extremely high mortality rates. Please note that the use of statin drugs and COX-2 inhibitors for cancer is considered an off-label use of these drugs. You may ask your doctor to prescribe one of the following statin drugs to inhibit the activity of Ras oncogenes:

  • Mevacor (lovastatin), 40 mg twice a day or
  • Zocor (simvastatin), 40 mg twice a day or
  • Pravachol (pravastatin), 40 mg once a day


In addition to statin drug therapy, consider supplementing with the following nutrients to further suppress the expression of Ras oncogenes:

  • Fish Oil Capsules: 2400 mg of EPA and 1800 mg of DHA a day. (Six Mega EPA fish oil capsules provide this potency.)
  • Green Tea Extract: 1500 mg of tea polyphenols a day. (Five Super Green Tea Extract Caps provide this potency.)
  • Aged Garlic Extract: 2000 mg a day. (Two Kyolic One Per Day caplets provide this potency.)


Should Antioxidants Be Taken at the Same Time as Chemotherapy?

There is a controversy as to whether cancer patients should take antioxidant supplements at the same time that cytotoxic chemotherapy drugs are being administered.

Proponents of antioxidants point to human studies showing that antioxidant supplements protect healthy cells from the damaging effects of chemotherapy drugs. Chemotherapy drugs can cause lethal heart muscle damage in a small percentage of cancer patients. Antioxidants such as vitamin E, coenzyme Q10 (CoQ10), N-acetyl-cysteine (NAC), glutathione, retinoids, ginkgo biloba, and vitamin C have been shown to specifically protect against chemotherapy-induced heart muscle damage (Tajima 1984; Mortensen et al. 1986; Iarussi et al. 1994; De Flora et al. 1996; D'Agostini et al. 1998; Schmidinger et al. 2000; Agha et al. 2001; Prasad et al. 2001; Blasiak et al. 2002). Other antioxidants have been shown to protect kidneys, bone marrow, and the immune system against chemotherapy toxicity.

Those who argue against antioxidant supplementation during chemotherapy are concerned that antioxidants will protect cancer cells against free-radical-induced destruction. Chemotherapy drugs work by varying mechanisms to induce cellular death. Some chemotherapy drugs kill cells by inflicting massive free-radical damage, while other chemotherapy drugs interfere with different cellular metabolic processes in order to eradicate cancer cells (and healthy cells as well). Depending on the type of cytotoxic drug used, however, antioxidants may confer protection to cancer cells during active chemotherapy.

The difficulty in reaching a consensus is that there are no controlled human or animal studies comparing the effects of various chemotherapy drugs, with and without antioxidants, against different cancers. The issue is complicated by studies showing that certain nutrients are associated with improved survival in cancer patients.

One problem is that there is little data to indicate whether supplements that have been shown to benefit the cancer patient should be taken during active chemotherapy. In other words, we know that anti-oxidants protect against chemotherapy side effects and may improve long-term survival in cancer patients, but do they lower the odds of achieving a long-term remission when administered during active chemotherapy?

Cancer patients contemplating cytotoxic chemotherapy are thus faced with a difficult dilemma. They can take antioxidant nutrients to protect their healthy cells against the toxic effects of chemotherapy, or they can avoid all antioxidants during chemotherapy to possibly improve the chances that the chemotherapy drugs will kill enough cancer cells to induce a complete response or cure.

To further complicate matters, certain supplements have proven mechanisms that could augment the cytotoxic efficacy of chemotherapy. For instance, curcumin has been shown to suppress growth factors that cancer cells use to escape eradication by chemotherapy drugs. (A complete description of curcumin's potential synergistic benefits with chemotherapy drugs appears later in this protocol.) The problem is that curcumin is also a potent antioxidant, and one recent animal study shows that curcumin could interfere with the cancer cell-killing effect of certain chemotherapy drugs. The scientists who authored this study pointed out that while curcumin has demonstrated potent effects in preventing cancer, its use during active chemotherapy is questionable because of its ability to protect cells against the type of molecular damage inflicted by these chemotherapy drugs (Somasundaram et al. 2002).

Critics of this study point out that the low dose of curcumin used in this animal study was adequate to provide antioxidant protection to the cancer cells but not high enough to suppress growth factors that enable cancer cells to escape regulatory control by the chemotherapy drugs. It was also pointed out that not all chemotherapy drugs kill cancer cells by generating free radicals. This means that curcumin may not hinder other chemotherapy drugs, as evidenced by remarkable tumor regressions found in other animal studies and human case histories.

Due to the multiple molecular complexities of this issue and the lack of specific in vivo studies, cancer chemotherapy patients are faced with choosing one of the following options:

Option One: Two weeks prior to the initiation of a chemotherapy regimen, discontinue all antioxidant supplements until 2-3 weeks after the last chemotherapy session. Most chemotherapy sessions are scheduled to last for 6-8 weeks.

The risk in depleting your body of antioxidants is that healthy cells will not be as well-protected against the toxic effects of chemotherapy. This means that depending on the chemotherapy drug therapy used, you could experience organ damage. You may also have increased immune impairment that could weaken your ability to fight the cancer. The toxic side effects of chemotherapy drugs can be the direct cause of death in some patients, long before the cancer kills them. Those who choose to deplete their body of certain antioxidants will also lose the potential benefit that these nutrients will help prevent cancer cells from developing escape mechanisms that enable these cells to develop resistance to chemotherapy and other anticancer drug(s). The potential benefit is that the chemotherapy drug(s) might work better if these antioxidants are not present.

Option Two: Continue taking antioxidant supplements recommended in this and the Cancer Adjuvant Treatment protocol before, during, and after the chemotherapy is administered.

The risk is that these antioxidants could interfere with the cell-killing effects of the chemotherapy drugs. This is no small risk because cancer patients who need chemotherapy usually have only one opportunity to eradicate enough cancer cells to experience a long-term remission or cure. Cancer cells not killed by the first round of chemotherapy are highly resistant to future chemotherapy and other therapies.

As stated earlier, it is important to note that not all chemotherapy drugs function by inducing free-radical damage to the cancer cells. In fact, many cytotoxic chemotherapy drugs function by alternative toxic actions such as interfering with DNA/RNA synthesis (the antimetabolites), disrupting the microtubular network (microtubule inhibitors), and inhibiting chromatin function (topoisomerase inihibitors)s. To help a cancer patient understand the mechanism of action of common cytotoxic chemotherapy drugs, we have provided Table 2.

Table 2: How Different Chemotherapy Drugs Kill Cancer Cells

Chemotherapy drugs that kill cancer cells by inflicting free-radical damage:
Drug
Trade Name
Mechanism of Action
Alkylating agents Free-radical damage
Busulfan
Carboplatin
Carmustine
Chlorambucil
Cisplatin
Cyclophosphamide
Ifosfamide
Procarbazine
Myleran
Paraplatin
BiCNU
Leukeran
Platinol
Cytoxan
Ifex
Matulane
 
Anthracyclines Free-radical damage
Bleomycin
Doxorubicin
Daunorubicin
Epirubicin
Mitomycin C
Blenoxane
Adriamycin
Cerubidine
Ellence
Mutamycin
 
Plant alkaloids Free-radical damage
Teniposide
VP-16
Vumon
Etoposide
 
Chemotherapy drugs that kill cancer cells by other mechanisms:
Drug
Trade Name
Mechanism of Action
Antimetabolites Inhibition of DNA/RNA synthesis
Asparaginase
Azacitidine
Cladribine
Cytarabine
Fludarabine
Fluorouracil
Hydroxyurea
Mercaptopurine
Methotrexate
Pentostatin
Ralitrexed
Thioguanine
Elspar
Mylosar
Leustatin
Cytosar
Fludara
Adrucil
Hydrea
Purinethol
Abitrexate
Nipent
Tomudex
Lanvis








(Analog of the vitamin folic acid)
Topoisomerase inhibitors Inhibition of chromatin function
Bleomycin
Dactinomycin
Daunorubicin
Doxorubicin
Epirubicin
Etoposide
Gemcitabine
Idarubicin
Irinotecan
Mitoxantrone
Plicamycin
Teniposide
Topotecan
Blenoxane
Cosmegen
Cerubidine
Adriamycin
Ellence
Vepesid
Gemzar
Idamycin
Camptosar
Novantrone
Mithramycin
Vumon
Hycamtin
Inhibition of topoisomerase II
Inhibition of topoisomerase II
Inhibition of topoisomerase II
Inhibition of topoisomerase II
Inhibition of topoisomerase II
Inhibition of topoisomerase II
Inhibition of topoisomerase I
Inhibition of topoisomerase II
Inhibition of topoisomerase I
Inhibition of topoisomerase II
Inhibition of topoisomerase II
Inhibition of topoisomerase II
Inhibition of topoisomerase I
Microtubule inhibitors Inhibition of chromatin function
Docetaxel
Paclitaxel
Teniposide
Vinblastine
Vincristine
Vinorelbine
VP-16
Taxotere
Taxol
Vumon
Velban
Oncovin
Navelbine
Etoposide




Mitotic arrest through binding of microtubules and spindle precursors
Mitotic arrest through binding of microtubules and spindle precursors

Table 2 provides some understanding of the mechanisms of action of chemotherapy drugs. Based on this information, it might appear that one could make a determination as to whether to take antioxidants based on the type of chemotherapy drug(s) used. Regrettably, there are other pathways (in addition to those listed) by which chemotherapy drugs induce cancer cell apoptosis that could be interfered with by taking the wrong dose of antioxidants. As already indicated, it is not possible to reach a scientific consensus as to which option to choose, that is, antioxidants or no antioxidants during active chemotherapy. There are too many variables such as the type of cancer, category of chemotherapy drug(s), molecular makeup of the cancer cells, individual variability, etc., to provide a conclusive recommendation for or against antioxidant supplementation during chemotherapy.

One reason for the uncertainty as to whether cancer chemotherapy patients should take antioxidants is the published studies showing that consumption of nutrients such as selenium and vitamin E can reduce the risk of contracting cancer. Cancer patients often take antioxidant supplements based on published studies showing that antioxidants help prevent cancer. Although some nutrients have been shown to reverse precancerous lesions, antioxidants by themselves are not a cure once full-blown cancer develops. There is persuasive evidence, however, that certain antioxidant supplements are effective in the adjuvant treatment of cancer. In other words, these supplements may help conventional therapies work better. What is missing is evidence of the effects of antioxidants in cancer patients undergoing aggressive chemotherapy.

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 a 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 are more resistant. The administration of the MTD also exposes healthy tissues to more damage.

Some studies indicate that a more scientific approach would be to lower the dose of conventional cytotoxic agents, reschedule their application, and combine chemotherapy drugs with antiangiogenesis agents to more 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. Endothelial cells then die with much less chemotherapy than conventional 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 endothelial cells the chance to recover. However, with tighter chemotherapy dose scheduling, the more 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 which 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 an 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 closely watched.

Continued . . .
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