|LE Magazine December 2000 |
LIFE EXTENSION TECHNICAL REPORT:
Suppressing cancer cell growth - a novel approach
Some readers may find this section somewhat technical, but it provides a stark example of how important it is to treat cancer patients along the revolutionary guidelines being proposed by The Life Extension Foundation.
How to make chemotherapy drugs work better
It has been established that “transforming growth factor” causes rapid cancer cell proliferation when it binds to the “epidermal growth factor receptor.” Overexpression of the “epidermal growth factor receptor” has been found in tumor cells that are resistant to cytotoxic drugs.
Iressa is classified as an “epidermal growth factor receptor inhibitor” that blocks signal transduction pathways implicated in cancer cell proliferation and other processes promoting cancer growth. One recent study(1) showed that Iressa induced a dose-dependent two- to four-fold increase in apoptosis (cell death) in all cancer cell lines tested. Iressa’s primary mechanism is to induce cell cycle arrest in the G1 phase. When Iressa was combined with various cytotoxic drugs (such as Taxol, cisplatin, carboplatin, Adriamycin), a supra-additive, growth inhibitory effect was observed on all doses.
This study showed that when human colon adenocarcinoma cell lines are transplanted into immunodeficient mice, Iressa suppressed tumor cell growth and significantly increased survival in the highest dose. Iressa functioned as a cytostatic, rather than cytotoxic agent, though an increase in programmed cell death (apoptosis) in higher doses was observed. When combined with cytotoxic drugs, Iressa induced a significant suppression of tumor growth as compared to untreated controls or to single agent-treated mice. The delayed growth observed in animals receiving Iressa plus cytotoxic therapy was accompanied by prolonged life span of mice that was significantly greater than untreated controls or single agent-treated animals. In one group treated with the cytotoxic drug Taxol plus Iressa, 40% of the mice were still alive 16 weeks after tumor injection (the only group to survive this long). Combined treatment did not induce signs of toxicity. Iressa thus demonstrated in vivo antitumor activity in immunodeficient mice with established tumor xenographs.
In the colon cancer test groups, the tumors in the untreated controls reached a size not compatible with normal life within four to six weeks after cell injection. In the single-agent group, tumor reached terminal size within six to eight weeks after cell injection. In contrast, in those animals receiving combination therapy (Iressa plus the cytotoxic drug), 50% of the animal where alive 10,12 and 15 weeks after cancer cell injection.
The scientists conducting this study speculated that in an attempt to increase survival and possibly eradicate established tumors, that additional cycles of combination Iressa and cytotoxic drug therapy could be administered. It was also noted that the mechanisms of action of Iressa seemed to be different than those of chemotherapy drugs used in combination. Iressa was shown to produce an enhanced effect when used with chemotherapy drugs that exert their cytotoxic effect via different structural mechanisms.
The results of this study are consistent with previous reports showing that a synergistic effect in the arrest of tumor growth when cytotoxic drugs are combined with an agent that blocks epidermal growth factor receptors such as Iressa. The beneficial mechanism postulated by the scientists who conducted this study is that cellular damage by chemotherapy can convert epidermal growth factor receptor ligands into survival factors for those cancer cells that express the epidermal growth factor receptor, ergo a reason why chemotherapy drugs often fail to induce long-term survival in the clinical setting. By blocking the epidermal growth factor receptor signaling pathway and other cell cycle growth factors, Iressa used in combination with cytotoxic drugs could cause irreparable cell damage, leading to the desired programmed cell death (apoptosis) of cancer cells.
In the clinical setting, the potentiation of the antitumor activity of cytotoxic drugs by interfering with epidermal growth factor receptor activation may make possible a reduction in the dose of chemotherapy drugs that normally cause systemic harm to the host. It may thus be possible to use Iressa to reduce the amount of toxic chemotherapy drug needed to achieve remission, and over a longer period of time, use Iressa to induce cancer cell apoptosis.
In order to ascertain the safety and efficacy of Iressa monotherapy, a study was conducted at four major cancer centers on a group of 58 patients with advanced disease. Ten of these patients had advanced head and neck cancers. In three out of nine head and neck cancer patients treated with low-dose Iressa (150 mg/day), a 20% reduction in tumor reduction occurred, with a 60% visual reduction of a large lip tumor and decreases in dermal metastasis. The conclusion of this study was that Iressa had acceptable tolerability, and produced antitumor activity when given as monotherapy. The findings of this study were presented at a cancer conference held last year.(2)
Iressa’s multiple mechanisms of action
According to a presentation published at a recent cancer conference,(3) the drug Iressa functions as a specific epidermal growth factor receptor tyrosine kinase inhibitor. The researchers stated that Iressa has demonstrated powerful antitumor activity both in vitro and in vivo and pointed to the following specific mechanisms of action to describe the drug’s antitumor effects:
- Iressa induced growth arrest of head-neck squamous cell carcinomas by inhibiting epidermal growth factor mediated cell signaling.
- Iressa induced a delay in cell cycle progression.
- Iressa induced a complete arrest of G1 phase cell growth after 72 hours of treatment.
- Iressa induced a time-dependent upregulation of the p27 cyclin-dependent kinase inhibitor.
- Iressa induced a dose-dependent decrease in cyclin-dependent kinase 2 activity within 24 hours of treatment.
These investigators noted that the combined effects of upregulating p27 and decreasing cyclin-dependent kinase 2 shed new light on how Iressa could favorably regulate cell-cycle machinery via growth factor receptor mediated signal transduction pathways, leading to further cell growth arrest.
Iressa in the treatment of squamous cell carcinoma
Treatment of squamous cell carcinoma by interferon-alpha has been successfully demonstrated.(4-8) At some point in the treatment, however, the tumor becomes refractory to the inhibitory effects of interferon and propagates out of control.(9)
Squamous cell carcinomas often exhibit an overexpression of the epidermal growth factor receptor.(10-12) Since upregulation of epidermal growth factor receptor is an escape mechanism to the antitumor effect of interferon-alpha, the concomitant use of the drug Iressa, which specifically blocks tyrosine kinase—the enyzme responsible for activating the epidermal growth factor receptor—appears to be a logical therapeutic approach to be used in cases where the primary squamous cell carcinoma has been significantly de-bulked using cytotoxic therapies, and the ultimate treatment objective is eradication of residual tumor using biological response modifiers like interferon-alpha.
Squamous cell cancers are often associated with high level overexpression of epidermal growth factor receptor, and therefore present a novel opportunity to use agents like Iressa in combination with proven biological response modifiers such as interferon-alpha, which have been shown to synergistically arrest cell growth. Investigators have proposed that the combined effects of Iressa and interferon-alpha on the induction of cancer cell growth arrest and apoptosis (programmed cancer cell death) is synergistic, and recommended that these two drugs (Iressa and interferon-alpha) be combined in a clinical study of advanced squamous cell carcinomas that are “epidermal growth factor receptor” positive as determined by The Foundation’s recommended cancer cell gene tests.(13)
A natural approach
Some Life Extension Foundation researchers have pointed to studies indicating that the herbal supplement curcumin also functions as an “epidermal growth factor receptor inhibitor.”(14-17) While these published studies are intriguing, especially as it relates to curcumin’s ability to prevent cancer, the Life Extension Foundation prefers to continue battling the establishment to allow cancer patients to immediately access drugs like Iressa that are supported by actual human clinical cancer trials.
Scientists have published results using Iressa alone and in combination with cytotoxic drugs that provide a rationale for Iressa to be prescribed in cancer patients with epithelial tumors that express functional epidermal growth factor receptors. The preliminary results from two Phase I studies demonstrate that Iressa may be administered over a prolonged period to cancer patients in doses sufficient to produce positive biological effectiveness with no major toxic effects.
Interferon-alpha has demonstrated efficacy in controlling squamous cell carcinomas, but interferon also induces epidermal growth factor, thus enabling cells overexpressing epidermal growth factor receptor to escape the antitumor effect of interferon-alpha.
In the in vivo model, Iressa and interferon have been shown to be synergistic, whereas combinations of cytotoxic drugs with Iressa are supra-additive. Thus, combining Iressa with the biological response modifier interferon-alpha, and/or cytotoxic chemotherapeutic agents, depending on the type of tumor involved, provides a practical opportunity to gain control over a particular cancer that would normally have a poor response rate.
Currently, clinical studies on Iressa are only planned for non-small cell lung cancer patients. To inquire about participating in these and possibly other studies, call AstraZeneca at 1-800-236-9933 or the Iressa expanded access program at 1-877-792-0518.
1. Clinical Cancer Research (Vol 6, 2053-2063;May 2000).
2. Proceedings of the 1999 AACR*NCI*EORTC International Conference (Meeting abstract #29).
3. Proceedings of the American Association of Cancer Research (Volume 41, March 2000).
4. Head Neck 2000 Mar;22 5(2):183-9.
5. Rom J Intern Med 1992 Jul-Sep;30(3):207-10.
6. Head Neck 1991 Jan-Feb;13(1):15-21.
7. Int J Clin Pharmacol Ther Toxicol 1991 Sep;29(9):342-6.
8. Rinsho Ketsueki 1991 Jul;32(7):786-90.
9. Anticancer Res 1988 May-Jun;8(3):467-9.
10. Head Neck 1992 Jan-Feb;14(1):8-13.
11. Head Neck 1991 Mar-Apr;13(2):132-9.
12. Head Neck 1989 Sep-Oct;11(5):437-42.
13. IMPATH Laboratories offers the immunohistochemistry tumor cell test that reveals what therapeutic agents are most likely to succeed. They can be reached at 1-800-447-5816.
14. Mol Urol 2000 Spring;4(1):1-6.
15. J Cell Biochem Suppl 1996;26:1-28.
16. Carcinogenesis 1995 Aug;16(8):1741-5.
17. Biochim Biophys Acta 1994 Dec 30;1224(3):597-600.