Designing an Individually Tailored Cancer Treatment Utilizing Advanced CTC Molecular AnalysisApril 2010
By Steven Nemeroff, ND
The Battle is Fought at the Cellular Level
Chemotherapy drugs can interact with cancer cells in various ways. These crucial interactions can decide the winner in the battle between the cancer and the chemotherapy drug. For example, some chemotherapy drugs only become fully activated after entering the cancer cell. This process is dependent upon the presence of certain enzymes within the cancer cell. A reduced production of these enzymes can lead to poor activation of the chemotherapy agent, resulting in a diminished anti-cancer effect. One chemotherapy drug which requires enzymatic activation is fluorouracil (5-FU), which is converted into its active form within the cancer cell by the enzyme uridine phosphorylase. Studies have shown that cancer cells resistant to 5-FU have a reduced expression of uridine phosphorylase.10,11
Gemzar® is a chemotherapy drug used in the treatment of lung, pancreatic, bladder, and breast cancer. Gemzar® requires the enzyme deoxycytidine kinase (DCK)—manufactured within the cancer cell—to become fully activated. Cancers that produce lesser amounts of DCK are protected from the effects of Gemzar®.12
Chemotherapy drugs can also exert their therapeutic effects by inhibiting essential enzymes within the cancer cell. The overexpression of these enzymes—called drug targets—can enhance the tumor destructive effects of these drugs. Adriamycin® (doxorubicin) is a prime example of this mechanism of action. The main drug target for Adriamycin® is topoisomerase 2. Studies have demonstrated that those patients with cancers expressing higher levels of topoisomerase 2 can benefit from treatment with Adriamycin®.13
Cancer cells also have the ability to produce enzymes that convert chemotherapy drugs into less potent forms, which weakens the anti-tumor activity of these drugs. 5-FU is commonly used in the treatment of breast and colon cancer. Dihydropyrimidine dehydrogenase (DPD) is an enzyme that degrades 5-FU to an inactive metabolite. Cancer cells expressing higher levels of DPD can be resistant to 5-FU. One study of colorectal cancer patients treated with 5-FU revealed that those with high DPD levels had significantly shorter overall survival compared to patients with low DPD expression.14
Cyclophosphamide (Cytoxan®) is utilized in the treatment of lymphoma, leukemia, and cancers of the breast, ovary, and bladder. Cancer cells produce an enzyme called gamma-glutamylcysteine synthetase (GCS), which metabolizes and inactivates cyclophosphamide. Cancer cells that manufacture greater amounts of GCS can possess a tactical advantage in the battle against cyclophosphamide.15
Other genetic expressions within the cancer cell can have a significant impact upon the effectiveness of chemotherapy drugs. The platinum drugs—cisplatin, carboplatin, oxaliplatin—are used in the treatment of ovarian, bladder, testicular, and lung cancer. These drugs inflict damage upon the cancer cell by attacking DNA. Cancer cells produce the excision repair cross-complementation 1 (ERCC1) protein, which is able to repair the damage caused by these drugs. Greater production of ERCC1 offers cancer cells a degree of immunity from platinum drugs.
A team of researchers in Italy measured ERCC1 mRNA levels in lung cancer patients receiving cisplatin.16 The researchers found a dramatic difference in survival based on the levels of ERCC1. Patients with cancers expressing lower levels of ERCC1 had a median overall survival of 23 months, compared to a median overall survival of 12.4 months in those with higher ERCC1 levels.
Methotrexate is a member of the “one size fits all” chemotherapy regimen for breast cancer. Methotrexate wields its tumoricidal activity by blocking an enzyme within the cancer cell called dihydrofolate reductase (DHFR). Cancer cells can compensate by producing more DHFR. Overproduction of DHFR provides cancer cells with a defense against methotrexate.17
In the battle against chemotherapy drugs, some cancers have developed a very clever mechanism to shift the balance of power in their favor. Multidrug resistance 1 (MDR1) is able to conveniently transport chemotherapy drugs out of the cancer cell, which drastically reduces their cancer-killing ability. Cancers that generate greater amounts of MDR1 are resistant to multiple chemotherapy drugs, such as vincristine, Taxol®, mitomycin C, and Adriamycin®.18,19
As an added benefit, genetic analysis of CTC can inform us as to which natural supplements might be best indicated. For instance, nuclear factor-kappaB (NF-kB) promotes the growth of cancer. Curcumin is an inhibitor of NF-kB.20 So, a person whose cancer is expressing high levels of NF-kB might consider including curcumin as part of their supplement program.
Some cancers are able to produce glutathione S-transferase pi (GST-pi), which confers resistance to multiple chemotherapy drugs. Ellagic acid—from pomegranate—inhibits GST.21 Supplementation with ellagic acid may be wise if CTC analysis demonstrates overproduction of GST-pi.
Advanced CTC Analysis is Now Available
When taking into consideration the numerous characteristics of the cancer that create its unique genetic fingerprint, we can now fully appreciate the radical differences that can occur between individuals with the “same” cancer, which may require distinctly different treatments. CTC analysis can now allow medical science to take the next step in cancer treatment by uncovering the key distinctions within the cancer—which ultimately distinguishes those with the “same” cancer from one another. The results of CTC analysis can help to ensure the design of a therapy best suited for an individual’s cancer. Fortunately, advanced CTC assays are now available.
For assistance in facilitating the advanced circulating tumor cell (CTC) molecular analysis available at European laboratories, you can contact the International Strategic Cancer Alliance (ISCA) at 610-628-3419.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
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