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Natural Chemotherapy Active Support Technology (CAST).

Chemotherapy: A Weapon Against Tumor Growth Chemotherapy is the tool of choice to slow down the evolution of most cancers. Successful chemotherapy will track and kill all cancer cells while avoiding attacking the healthy cells of one's organism. Unfortunately, this therapeutic ideal is seldom attained because cancer cells naturally have certain means to resist the action of chemotherapeutic agents. (5)

Chemotherapy and Resistance

In fact, cancer cells generally react well to a first round of chemotherapy. Their number decreases to a level where their presence cannot be detected any more and the patient is then considered in remission. This more or less long calm spell unfortunately is still too often followed by a relapse (See Figure 1). However, some cancer cells -- more resistant than average -- can indeed survive the first offensive of chemotherapy. Being very few, they are not easily detectable up to the moment when, having recovered from chemotherapy in-suits, they start dividing at a fast pace. Reapplying the initial therapeutic protocol generally turns out to be ineffective on these cells, and increasing doses may exacerbate side effects to an unacceptable level. Even opting for a different arsenal of chemotherapeutic agents may not make it possible to break this resistance. The cancer cells have now developed resistance to multiple chemically and functionally unrelated anti-tumor compounds. (3) This phenomenon is called multi- drug resistance.

What is the Molecular Mechanism Underlying This Drug Resistance?

A major reason for such drug resistance is the presence of proteins called P-gp within the membrane of the cancer cells. (4) P-gp proteins are pumps that actively extrude the "activated" chemotherapeutic agents from the interior of the cancer cells to the extracellular space where they can no longer exert their anti-tumor action (See Figure 2). By preventing accumulation of drugs inside the cancer cells, P-gp pumps' action seriously impairs the efficacy of treatments. (6) Moreover, this pump is not very selective and will expel the vast majority of chemotherapeutic agents encountered, leaving very few therapeutic options whenever the cancer cells express much P-gp. (4)

One of the negative effects of chemotherapy is the selection for survival of cancer cells overexpressing P-gp from an initially heterogeneous population for P-gp expression. (1) The cells overexpressing P-gp pumps indeed manage to survive the initial chemotherapy, possibly to form a new clonal population of cancer cells, from now on refractory to most chemotherapeutic agents (See Figure 3). Chemotherapy resistance is established.

CAST Biological Actions

CAST (Chemotherapy Active Support Technology) is a multivalent all-natural vegetarian formula acting as a chemosensitizer and an inhibitor of matrix metalloproteinases (MMPs) as well. The CAST ingredients were judiciously selected for their synergistic action in order to achieve optimal support for chemotherapy. Inclusion of a proprietary ingredient (AOMC) makes CAST a unique formula. Moreover, the various levels of solubility of CAST ingredients make it possible to saturate simultaneously both aqueous and lipidic pools of the human body.

CAST Chemosensitizing Activity

The main strength of CAST resides in its ability to inhibit P-gp pump activity in cells. An in vitro study showed that the drug binding properties of P-gp toward the representative chemotherapeutic agent iodoarylazidoprazosin (IAAP) were inhibited by 86% in the presence of CAST (See Figure 4), as detected by a photoaffinity technique. Since drug binding to P-gp is mandatory for drug extrusion through the pump, inhibition of IAAP binding on P-gp reflects the inhibition of P-gp pumping activity.

Based on these results, CAST is expected to act as a valuable therapeutic support. By inhibiting P-gp pumps activity, CAST will allow chemotherapeutic agents to accumulate within the cancer cells to better exercise their anti-tumor action (See Figure 5). In fact, not only should CAST preserve the sensitivity of the cancer cells towards chemotherapeutic agents, such as vincristine, doxorubicin, vinblastine and etoposide (among others), but it is expected to even restore it where lost, such as in chemotherapy refractory tumors. (7)

CAST Inhibition of MMP Activity

Sensitizing tumor cells to chemotherapeutic agents is not the only mode of action of CAST. This multipotent product also has the potential to help prevent cancer dissemination by antagonizing the action of some metalloproteinases, as shown in an in vitro assay for MMP-2 activity. The inhibitory effect of CAST towards the gelatinolytic activity of MMP-2 was confirmed using a fluorescence-based in vitro assay (See Figure 6). In this assay, a purified MMP-2 enzyme is incubated in the presence of a fluorogenic substrate with and without CAST. The MMP-2 activity can be measured through the reading of the emitted fluorescence. This experiment demonstrated that CAST inhibited MMP-2 activity by 90%.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which can degrade the major components of the extracellular matrix (ECM). Cancer cells subvert MMP activity to promote invasion of the surrounding tissues, as well as metastasis to distant ones (See Figure 7). MMPs, by releasing growth factors sequestered in the extracellular matrix, also are thought to promote the growth of these tumor cells once they have metastasized. (2) Thus by opposing MMP-2 activity, CAST may prevent tumor progression and metastasis.

Conclusion

The strength of CAST is in its multivalent approach to support cancer treatment. First it inhibits the activity of the P-gp pumps. Knocking down this resistance mechanism maintains the chemotherapeutic agents within the tumor cells where they can fully express their anti-tumor action. This ensures that every tumor cell receives its due dose of chemotherapeutic agents regardless of how many P-gp pumps it may express. Making all tumor cells equal in the face of chemotherapy may further prevent the appearance of chemotherapy resistance. Second, inhibiting the proteolytic activity of MMP-2 on the collagen matrix prevents the switch to a more invasive type of cancer. Maintaining the cancer cells' sensitivity to therapeutic agents and preventing the growth of tumors and the development of metastasis will greatly improve the overall rate of survival among cancer patients under a chemotherapeutic regimen.

[Figure 1 Omitted]

[Figure 4 Omitted]

[Figure 6 omitted]

REFERENCES

(1.) Bosch I and Croop J. "P-glycoprotein multidrug resistance and cancer." Biochim Biophys Acta, Oct 9, 1996; 1288(2):F37-54.

(2.) Chang C and Werb Z. "The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis," Trends Cell Biol, Nov, 200l;l1(1l):S37-43.

(3.) Ford JM. "Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers." Eur J Cancer, 1996; 32A:991-l00l.

(4.) Lehne G. "P-glycoprotein as a drug target in the treatment of multidrug resistant cancer." Gurr Drug Targets, 2000; 1(l):85-99.

(5.) Links M and Brown R. "Clinical relevance of the molecular mechanisms of resistance to anti-cancer drugs," In: Expert Reviews in Molecular Medicine. Cambridge University Press, 1999; http://www-ermm.cbcu.cam.ac.uk.

(6.) Shustik C, Dalton W, and Gras P. "P-glycoprotein-mediated multidrug resistance in tumor cells: biochemistry, clinical relevance and modulation." Molec Aspects Med, 1995; 16:1-78.

(7.) Sikic BI, Fisher GA, Lum BL, Halsey J, Beketic-Oreskovic L, and Chen G. "Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein." Cancer Chemother Pharmacol, 1997; 40 Suppl:S13-9.

About the Author

Alain Thibodeau, PhD, received his Master's in Biochemistry and holds a doctorate in Molecular and Cell Biology from Laval University, Canada. He also completed postdoctoral studies in Cellular Physiology at the University of California at Berkeley. He is the director of scientific affairs at Atrium Biotechnologies. Dr. Thibodeau is the author of several published scientific articles. He is a frequent lecturer and author worldwide for the natural health care industry and specifically in the fields of dermatology, angiogenesis and immunity. If you would like more information, email info@cast-technology.com
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Author:Thibodeau, Alain
Publication:Original Internist
Date:Mar 1, 2002
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