Integrative Regulatory Therapy Research

Chapter 12: IRT Specific Drugs for Cancer Control

Oasis of Hope IRT protocols, in addition to including a range of anti-inflammatory adjuvant drugs, also include several other drugs that usually are not considered anti-inflammatory. These include the drugs cimetidine and valproic acid, each of which has been used safely for decades. We also use drugs that modulate sex hormone activities in patients who have hormone-sensitive breast or prostate cancers. The following provides and explanation.

Cimetidine

Cimetidine, also known as Tagamet, has been in wide use for many years as a treatment for gastrointestinal ulcers. It functions to suppress production of gastric acid by blocking so-called H2 receptors for the hormone histamine. In 1988, Danish researchers reported that, in patients with gastric cancer, concurrent cimetidine therapy was associated with improved survival (1). Since then, cimetidine has been reported to improve survival in patients with colorectal cancer (2,3) and occasional objective responses have been observed in patients with melanoma or renal cell cancer treated with cimetidine alone or in conjunction with the anti-coagulant drug coumari. (4,5). Cimetidine has also shown growth-retardant effects on certain cancers in rodents (6,7). It was initially suspected that these benefits reflected a significant role for histamine as an immunosuppressive or growth-stimulant hrmone in clinical cancer.

However, cancer clinical studies evaluating other anti-ulcer drugs that block H2 receptors failed to show survival benefits, suggesting that the favorable responses to cimetidine might reflect an idiosyncratic effect of this drug unrelated to histamine antagonism (8,9).

Since the incidence of metastases was found to be substantially decreased in colorectal cancer patients treated with cimetidine, Japanese researchers suspected that cimetidine might influence the capacity of cancer cells to bind to endothelial cells, an essential step in the formation of new metastases. They were in fact able to demonstrate that clinical concentrations of cimetidine did inhibit the adhesion of certain cancer cells to endothelial cells. This reflected cimetidine’s ability to suppress endothelial expression of a key adhesion protein known as E-selectin (10). E-selectin is able to bind to certain types of complex carbohydrate chains that are frequently expressed on the surfaces of cancer cells that have the capacity to metastasize, but not by the healthy tissues from which they arise (11). In fact, the Japanese researchers were able to demonstrate that cimetidine treatment only improved the survival of colorectal cancer patients whose tumors expressed these types of carbohydrate chains (3). Moreover, they showed that pre-treatment with cimetidine suppressed the formation of liver metastases in mice injected with cancer cells (10). So it seems that cimetidine makes endothelial cells more "slippery" by suppressing the E-selectin adhesion protein, thus making it harder for cancer cells circulating in the bloodstream to bind to the endothelial lining of blood vessels. Other H2-antagonist anti-ulcer drugs did not influence E-selectin expression by endothelial cells – consistent with the failure of these drugs to influence survival in clinical cancer (10).

One fascinating clinical study concluded that administration of cimetidine for only a one-week period, prior to and following surgery, improved the prognosis of colorectal cancer patients (12). This likely reflects the fact that the inflammatory response triggered by surgery induces increased expression of E-selectin by endothelial cells, while surgery also can dislodge cancer cells, increasing the number of such cells circulating in the blood. (11). So the days immediately following surgery may be associated with high risk for new metastasis formation. Cimetidine administration at this time may thus be particularly protective.

This "slippery endothelium" hypothesis helps to explain how cimetidine works to prevent metastases and prolong survival in many types of cancer. However, it doesn’t completely explain cimetidine’s impact on cancer, because in some animal studies cimetidine has slowed the growth of the primary tumor. This appears to reflect an inhibitory impact of cimetidine on the angiogenic process that is essential for the growth of solid tumors. Thus, one recent study shows that, in mice bearing transplanted colon cancers, cimetidine therapy decreases the vascularity of the tumor (13). Cimetidine did not lessen the ability of the cancer cells to make angiogenic factors (hormone-like agents that activate angiogenesis), so it seemed to be acting directly on endothelial cells. Indeed, clinical concentrations of cimetidine were shown to diminish the capacity of endothelial cells in culture to roll themselves into tubes - a necessary step in the formation of new capillaries. This is likely because of its impact on endothlelial expression of E-selectin (14).

Cimetidine has been in use for a number of years. It is generally well tolerated, and appears to be quite safe. The dose schedule we are using in cancer care is the same as that approved for use in prevention and treatment of ulcers. However, high doses of cimetidine have the potential to increase estrogenic activity by blocking the CYP450 enzyme that metabolizes estrogens. Occasional cases of gynecomastia (inappropriate breast growth) have been reported in males treated with high doses of this drug (15). For this reason, Oasis of Hope chooses not to use cimetidine in women with estrogen-sensitive breast cancers.

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Valproic Acid

Valproic acid is a member of a class of drugs known as "histone deacetylase inhibitors" that have recently shown versatile anti-cancer effects in animal studies. Acetylation, in which chemical structures known as acetyl groups are enzymatically linked to proteins is often required for efficient transcription of genes. Transcription is the process whereby nuclear DNA is used as a template for production of messenger RNA which in turn serves as a template for synthesis of new proteins. Acetylation of DNA-binding proteins known as histones usually aids the transcription of genes. Proteins known as co-activators promote acetylation of histones near specific genes to promote their transcription. However, it is sometimes physiologically desirable to suppress gene transcription, so cells also produce enzymes known as histone deacetylases (HDACs). As their name implies, they remove the acetyl groups from histones and other acetylated proteins.

In many cancers, anomalously decreased transcription of certain genes, known as suppressor genes, contributes to the malignant behavior of cancer. These genes code for proteins that have anti-proliferative effects in the cell. Some years ago, it occurred to cancer scientists that excessive or inappropriate HDAC activity might be responsible for the suppressed transcription of certain suppressor genes. They reasoned that, if this were the case, drugs which inhibit HDACs might boost the transcription of these suppressor genes and thereby make the cancer less aggressive and more controllable. When they treated cancer cells with chemicals that could inhibit HDAC, they were gratified to observe that the cancer cells often decreased their rate of multiplication, were more prone to apoptosis, and were easier to kill with cytotoxic cancer drugs. In some cases, the drugs had a "redifferentiating" effect, meaning that the cancer cells looked and acted more like the healthy tissues from which they were derived. In mice transplanted with human cancers, treatment with HDAC inhibitory drugs slowed cancer growth and increased the efficacy of cytotoxic chemotherapeutic drugs or radiotherapy (16-22).

However, the researchers were surprised to find that increased expression of proteins coded by suppressor genes usually was not clearly responsible for these benefits of HDAC inhibitors. In fact, many proteins inside and outside the nucleus are susceptible to reversible acetylation, and so HDAC inhibitors may be influencing the structure and function of a great number of regulatory cellular proteins by boosting their acetylation.

Why HDAC inhibition tends to have such a favorable effect on the behavior of cancer cells remains unclear and is a subject of active investigation. Perhaps one way to look at it is this: the unregulated growth and relative invincibility of cancer cells reflects a carefully balanced regulatory system. Treating with HDAC inhibitors is rather like throwing a monkey wrench into this mechanism, inducing an alteration of cellular behavior. Fortunately, this alteration tends to be positive for the patient. Moreover, HDAC inhibitors tend to be well tolerated, having comparatively little impact on the function or viability of most healthy tissues (23).

Remarkably, HDAC inhibitors also have anti-angiogenic effects, acting directly on endothelial cells to slow the development of new blood vessels required for cancer growth and spread (24-26). These drugs can also suppress tumor production of certain angiogenic factors, notably vascular endothelial growth factor (VEGF), which are crucial stimulants to tumor angiogenesis (27). This latter effect is at least partly attributable to decreased activity of a protein (transcription factor) known as hypoxia-inducible factor-1, which promotes the angiogenic process in poorly oxygenated tumors (28,29). Yet a further benefit is that HDAC inhibitors can increase cancer cell production of certain membrane proteins that help NK cells and cytotoxic lymphocytes bind to and target cancer cells (30). So HDAC inhibitors can provide a versatile range of benefits in cancer therapy.

German researchers discovered a few years ago that a time-tested anti-epileptic drug, valproic acid, acts as a HDAC inhibitor in concentrations that can be achieved clinically (31-33). Furthermore, aside from the fact that valproic acid sometimes produces mild sedation, it is usually quite well tolerated, and thus could be suitable for long-term use in the management of cancer. Experimental studies have confirmed that valproic acid has the cancer retardant and anti-angiogenic effects seen with other HDAC inhibitors (25,31,34-39). As contrasted with other agents that are being developed as new drugs for HDAC inhibition, valproate has the merit of being currently available, with an acceptable side effect profile that is well known, and it is a relatively inexpensive old drug.

Cancer scientists in Mexico City have already conducted a Phase I study of valproic acid as a cancer drug (40). This study confirmed that administration of valproic acid in a clinically tolerable dose range was able to increase the acetylation of histone proteins in the majority of patients, showing that this drug does indeed function as an HDAC inhibitor in humans when administered in feasible amounts. We currently use a dose range of 1,500-2,000 mg daily, which is within the range validated in this study.

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Hormone Blocking Agents

Some cancers are dependent on specific hormones for optimal growth and survival. For example, many breast cancers require estrogen, and are said to be estrogen-sensitive. Analogously, many prostate cancers require testosterone to grow and thrive. This is especially true during the earlier stages of the disease. That’s why medical science has developed specific drugs that can inhibit the production or activity of these sex hormones, for use in cancer therapy. This strategy has become a standard part of cancer management, with well-documented benefits for controlling cancer spread and prolonging patient survival. So these hormone-blocking drugs are included in the IRT protocols for hormone-dependent breast and prostate cancers. The good news about these agents is that they don’t have the range of side-effects that cytotoxic chemotherapies have. The unavoidable bad news about them is that loss of estrogen in women, and of testosterone in men, can have undesirable physiological effects. In particular, men lose sexual potency when deprived of testosterone. Many of our patients with hormone-sensitive prostate cancer choose not to use testosterone-blocking drugs. As is always the case at Oasis of Hope, the patient is the final arbiter regarding the therapy that he or she receives. With respect to estrogen-sensitive breast cancers, our therapeutic approach depends on whether the woman is pre- or post-menopausal.

In pre-menopausal women with estrogen-sensitive breast cancers, we standardly use the drug tamoxifen, which binds to the estrogen receptor in a way that diminishes its growth-promoting activity in breast cancers. Tamoxifen is known as an estrogen antagonist, because it prevents estrogen from binding to the receptors that mediate its hormonal activity. The use of tamoxifen effectively entails the induction of menopause in pre-menopausal women. This is unfortunate. But menopause is part of the natural life cycle in any case, so most women learn to live with this. Tamoxifen is generally considered a safe drug, though its long-term use does increase risk for cancers of the uterine endometrium.

In post-menopausal women, the ovaries are no longer generating estrogens. Nonetheless, a certain amount of estrogen is still produced in fat cells. Fat cells (adipocytes) contain an enzyme called aromatase that can convert circulating androgens to estrogen. Please note that healthy women normally produce very small amounts of "male" hormones. Drugs known as aromatase inhibitors can inhibit this fat-mediated conversion of androgen to estrogen, and so can greatly reduce estrogen levels in post-menopausal women. They don’t influence ovarian production of estrogen in pre-menopausal women, and so aren’t used in pre-menopausal patients. Studies show that aromatase inhibitors do a better job than tamoxifen for slowing or reversing the spread of estrogen-sensitive breast cancers in post-menopausal women, so this is the option which Oasis of Hope uses in the management of estrogen-sensitive post-menopausal breast cancer (41). Several different aromatase inhibitors are now available for clinical use – with generic names like "anastrazole or "letrozole." Since it is not yet clear which of these drugs is clinically superior, our doctors use their own judgment in choosing them. Aside from the fact that these drugs induce a loss of estrogen activity, they are well tolerated.

Years ago, the traditional therapy for testosterone-dependent prostate cancer was a surgery known as "orchiectomy," which is the medical term for castration. Because this was a less than popular option with most patients, pharmaceutical companies have developed drugs that can inhibit the function or production of testosterone, while allowing the patient to keep his testicles. Not surprisingly, this strategy has proved much more popular, and is the approach we recommend at Oasis of Hope.

Two drug-based strategies are commonly used for suppressing testosterone activity in androgen-dependent prostate cancer. One of these is to block the testosterone receptor with a drug such as Casodex, also known as bicalutimide. This approach is quite analogous to the use of tamoxifen in estrogen-sensitive breast cancer.

The drug binds to the androgen receptor in a way that inhibits its activity. An alternative approach is to suppress testicular testosterone production with a drug that works on the brain to block its production of a hormone known as luteinizing hormone (LH).

LH activity is crucial for efficient testosterone production by the testes. The drugs most commonly used to achieve this are known as luteinizing hormone releasing hormone (LHRH) agonists, because they mimic the activity of LHRH, a brain hormone that stimulates LH release (42).

One would think that such drugs would increase LH release – and in fact they do so temporarily – but prolonged continual use of these drugs actually causes a sustained decrease in LH release, owing to the fact that the brain loses its sensitivity to LHRH stimulation. The LHRH agonist drugs that are currently available are goserelin (Zoladex) and leuprolide (Lupron). They are injected in depot formulations once every several months.

The loss of LH activity associated with the prolonged use of LHRH antagonist drugs causes a temporary atrophy of the testes. The good news is that, after these drugs are discontinued, testosterone production usually returns to normal levels within 18 months (43).

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