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Property "Has original text" (as page type) with input value "Fish oil (source of omega-3 fatty acids)
The major omega-3 fatty acids found in cold-water fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have also been demonstrated to have potent cytotoxic effects on cancer cells in various laboratory experiments. Part of their mechanism of action is similar to that of GLA, in that the metabolism of these fatty acids creates high levels of free radicals. In addition, a recent laboratory study has shown that EPA-treated tumors showed a significant arrest of cell division due to inhibition of cyclins at the G1 phase of cell division, which resulted in an increased rate of programmed cell death known as apoptosis (241).
A clinical trial comparing fish-oil supplements versus a placebo has also been reported, involving patients with several different types of advanced cancer (242). Thirty malnourished patients suffering from cachexia were randomly assigned to receive 18 g of fish oil per day or a placebo sugar pill. An additional thirty subjects, adequately nourished, received a similar random assignment. For both groups the fish oil significantly increased survival. For the malnourished patients the median survival times, as estimated from their survivor functions, were 110 days for the patients receiving placebo and 210 days for patients in the fish oil group. For the adequately nourished patients, the corresponding numbers were 350 versus 500 days.
In laboratory studies (243) fish oil has also been shown to increase the effectiveness of chemotherapy and radiation. A phase II trial involving 25 heavily pretreated metastatic breast cancer patients, used 1.8 g/day of DHA, one of the two major fatty acids in fish oil, in combination with standard anthracycline-based chemotherapy (244). Patients previously had failed both chemotherapy and hormone treatments and many had multiple metastases, including many liver metastases. Because this was a phase II trial, there was no control group that received chemotherapy alone, but patients were subdivided according to their level of plasma DHA. The two groups were approximately equal with respect to all major prognostic variables. Median survival for the high DHA patients was 34 months, vs. 18 months for the low-DHA patients.
A second clinical trial presented 2200 mg of EPA plus 240 mg of DHA to patients with advanced non small cell lung cancer (245). Patients either received only the standard of care of chemotherapy, or the same treatment in combination with daily fish oil. Response rate (tumor regressions) was 60% in the fish oil group and 26% in those receiving only the standard of care. One-year survival was 60% in the fish oil group versus 39% in those receiving only chemotherapy. Chemotherapy toxicity was also decreased in those using fish oil." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "Silibinin (an ingredient of Milk Thistle)
Silymarin is an extract from the milk thistle plant that has been used extensively in Europe as an antidote for liver toxicity, due to mushroom poisoning and overdoses of tylenol. Its active ingredient is a molecule called silibinin. Recently a great deal of laboratory research has shown it to have anti-cancer effects, which recently have been reviewed (275). Like genistein and quercetin it is a tyrosine kinase inhibitor, but it appears to have multiple other effects, including the inhibition of the insulin-like growth factor (IGF) that contributes to the development of chemoresistance (276) (see the section on tamoxifen), and the inhibition of angiogenesis (277). It also inhibits the 5- lipoxygenase inflammatory pathway and suppresses nuclear factor kappa B, which is a primary antagonist to apoptosis (278). It also appears to protect against common chemotherapy toxicities (279), while at the same time increasing the effectiveness of �chemotherapy." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "Sulforaphane
This naturally occurring compound has shown promise in the laboratory for its ability to target and weaken cancer cells, particularly glioblastoma cells. It functions by inhibiting pathways that cancer cells use for growth and survival, potentially enhancing the responsiveness of these cells to treatments like chemotherapy and radiotherapy. Its role in cancer treatment, while still being evaluated, underscores the potential for using dietary compounds in a supportive or adjunctive therapy role." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "Numerous laboratory studies have shown that Vitamin D is highly cytotoxic to cancer cells, due to several different mechanisms (although labeled as a vitamin it more properly should be considered a hormone). While most research has focused on its ability to activate genes that cause cancer cells to differentiate into mature cells, other effects have also been identified, including cell cycle regulation, inhibition of the insulin-like growth factor, and the inhibition of angiogenesis (246). However, the calcitriol form of Vitamin Dis not readily usable for cancer treatments because the dosages producing anti-cancer effects also cause hypercalcemia, which can be life threatening (the major function of Vitamin D is to regulate calcium absorption and resorption from the bones and teeth). But like many vitamins/hormones, the generic designation refers not to a specific chemical structure but to a family of related molecules that may have different properties of various sorts. For Vitamin D several of these variants (commonly referred to as analogues) have been shown to effectively inhibit cancer cell growth but without the same degree of toxic hypercalcemia. In a 2002 paper in the Journal of Neuro-oncology (247), 10 patients with glioblastoma and one with a grade III AA tumor received a form of Vitamin D called alfacalcidol in a dosage of .o4 micrograms/kg each day, a dosage that produced no significant hypercalcemia. The median survival was 21 months, and three of the eleven were long-term survivors (greater than 5 years). Although the percentage of patients who responded to the treatment was not high, the fact that any relatively non-toxic treatment can produce any number of long-term survivors is remarkable. There is also strong reason to believe that Vitamin D is synergistic with retinoids such as accutane (248). Its effectiveness is also increased in the presence of dexamethasone (249) and a variety of anti-oxidants, notably carnosic acid, but also lycopene, curcumin, silibinin, and selenium (250).
Alfacalcidol is not available in the USA, but is available in Europe and Canada. For those in the USA it is possible obtain it from various online marketers. It also should be noted that several other Vitamin D analogues are available, which also have much reduced hypercalcemic effects. One of these, paricalcitol, was developed for treatment of a disorder of the parathyroid gland, and recently has been the subject of several experimental studies (251, 252, 253) that have shown it to be highly cytotoxic to 34
many different types of cancer. Given that other forms of Vitamin D have been shown to be highly cytotoxic to for glioblastoma cells, and that glioma cells are known to have receptors for Vitamin D, it seems likely that paricalcitol should have efficacy for glioblastoma as well. Unfortunately, its routine use is complicated by the fact it is available only in a form that requires intravenous injection.
The most common version of Vitamin D3 found in health food stores is cholecalciferol, which is the precursor of calcitriol, the form of Vitamin D utilized by the body. A recent study of cholecalciferol with prostate cancer patients who had progressed after standard therapy (254) suggests that this common form of Vitamin D3 may be clinically beneficial. Fifteen patients who had failed standard treatments were given 2000 I.U. daily. PSA levels were reduced or stayed the same for nine patients, and there was a reliable decrease in the rate of PSA increase for the remainder. No side effects of the treatment were reported by any of the patients.
Because serum Vitamin D levels have recently been shown to be inversely related to cancer incidence, there recently has been considerable discussion about the dosage that is toxic. Doses as high as 5000-10,000 I.U. per day appear to be safe. Recently, it has become common for women suffering from osteoporosis with low Vitamin D levels to be given as much as 50,000, I.U./day for short time periods. Nevertheless, it is important to note that all forms of Vitamin D can occasionally produce dangerous serum calcium levels, in part because there is a great deal of variability in their effects across individuals. It is thus important that blood calcium levels be monitored, especially while a nontoxic dosage is being established." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "A very different approach to developing a treatment vaccine, which has the virtue of being usable "off-the-shelf”, without modification for individual patients, targets a mutation of the epidermal growth factor receptor, known as variant III, which occurs in 25-40% of GBMs. One reason that EGFR inhibitors such as Iressa have not been more effective is that they target the normal EGFR receptor, not this mutated receptor. EGFR variant III is also rarely seen in anything other than GBM tumors. To be eligible for the trial, patients must first be tested whether they possess the mutation.
Disappointing news was delivered by Celldex in a press release dated March 7, 2016, when the company announced that the phase III ACT IV clinical trial of rindopepimut for newly diagnosed glioblastoma patients with minimal disease would be discontinued, after an independent review board found that the trial was unlikely to meet its primary endpoint (improved overall survival). Although survival results were consistent with previous phase II trials, the control arm in this trial had survival outcomes that were better than expected (median overall survival was 20.4 months in the rindopepimut arm and 21.1 months in the control arm, hazard ratio = 0.99).
Rindopepimut is also being tested in a randomized phase II trial for recurrent glioblastoma called ReACT, in combination with Avastin. Data presented at the ASCO 2015 meeting showed that the primary endpoint of the trial (six month progression-free survival) was met. PFS-6 was 30% in the rindopepimut + Avastin arm, versus 12% in the control arm (per protocol). Additional data (reference 340, abstract IMCT-08) was presented later in 2015 at the SNO meeting, where it was reported that overall survival was also significantly improved and 2-year survival was 25% for the rindopepimut arm versus 0% in the control arm. Patients receiving rindopepimut had also reduced dependency on steroids, as 33% of patients were able to cease steroid treatment for six months or longer, versus none in the control group.
While the development of Rintega (rindopepimut) as a first-line treatment for GBM is
unlikely to continue given these trial results, the therapy still holds promise combined with Avastin in the recurrent setting, according to the outcomes of the ReACT trial." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
