Shorts

briefed by Jule Klotter

Aneuploidy in Cancer

For over 30 years, researchers have sought mutated regulatory genes (oncogenes), believed to cause cancer. The failure to find any oncogene whose presence, on its own, initiates cancer has pushed some researchers to reconsider a 100-year-old theory, first proposed by German scientist Theodor Boveri: the aneuploid cancer theory. The aneuploid theory focuses on chromosomes instead of genes. Normal human cells have pairs of 23 standard chromosomes (a diploid karyotype). All cancer cells, however, have highly irregular chromosome patterns (aneuploid karyotypes): “entire chromosomes, which carry thousands of genes, are … severely scrambled – duplicated, broken, structurally rearranged or missing entirely,” says molecular biologist Peter Duesberg in a 2007 article for Scientific American.

A missing chromosome means the genes it holds are also gone – genes that regulate the expression of important proteins. Conversely, extra copies of a chromosome means more copies of the genes and more of the corresponding polypeptides. “Such gross imbalances would inevitably disrupt the work of critical teams of enzymes, including those involved in repair or disposal of damaged DNA, and would destabilize cellular structures and regulatory circuits,” Duesberg explains. Usually, cells that become aneuploid during mitosis do not survive. Those that do will propagate increasingly irregular cells, eventually forming a tumor. “Once cancer progression is underway, random chromosome reshuffling can rapidly generate gratuitous traits that include lethal properties such as drug resistance and metastasis,” says Duesberg.

The aneuploid theory was tossed aside about 50 years ago because researchers were unable to detect any chromosomal patterns with available technology. New technology, however, lets researchers track chromosomal changes using colored DNA-specific probes. Research teams are finding chromosomal patterns in the same cancer types found in different people. Duesberg says these patterns may reflect essential chromosome changes needed to create a viable aneuploid cell from the original normal tissue. Researchers are also finding chromosomal patterns associated with cancer stage, metastatic potential, and drug resistance.

All carcinogens cause aneuploidy even though they may not cause genes to mutate. Asbestos, aromatic hydrocarbons, nickel, arsenic, lead, plastic and metallic prosthetic implants, and dioxin are among the carcinogens that disrupt chromosomes but do not cause gene mutation. Duesberg says, “The dose of carcinogen needed to initiate the process that forms malignant tumors years later was found to be less than one-thousandth the dose required to mutate any specific gene.”

If the aneuploid theory proves correct, diagnosticians will be able to distinguish early cancers from benign tumors by looking for aneuploidy. They will also be able to use chromosomal patterns to determine cancer cells’ metastatic potential and drug resistance. Moreover, regulators and manufacturers will be able to identify aneuploid-inducing substances before adding them to foods, drugs, and other consumer products.

Perhaps, cancer prevention can go even one step further and identify factors that decrease aneuploidy and encourage cells to remain diploid.

Duesberg P. Chromosomal chaos and cancer. Sci Am. May 2007;53–59. Available at www.davidrasnick.com/Cancer_files/Dues.Sci.Am.cancer.pdf. Accessed June 29, 2015.

Cancer Research

“Sadly, clinical trials in oncology have the highest failure rate compared with other therapeutic areas,” say C. Glenn Begley and Lee M. Ellis in their 2012 commentary for Nature. They attribute the high failure rate primarily to the published preclinical research that forms the groundwork for drug development. Even at its best, preclinical cancer research focuses on a limited number of tumor cell lines that cannot reflect the complexity of cancer found in a human being. Too often, however, these limitations are superseded by an even greater problem; the results of many “landmark” preclinical studies, offering new treatment avenues, cannot be reproduced.

When scientists at biotech firm Amgen’s hematology and oncology department reexamined 53 studies related to a proposed line of new research, they were dismayed that only 6 (11%) could be reproduced – even after contacting the original authors for directions. The 53 studies suggested new ways to use existing drugs or introduced novel treatment ideas. Amgen scientists expected some of them to fail but not the majority. Amgen is not the only company to encounter this problem. Bayer HealthCare (Germany) could reproduce the results of about 25% of the preclinical studies related to their own research and development projects. “In studies for which findings could be reproduced, authors had paid close attention to controls, reagents, investigator bias and describing the complete data set,” say Begley and Ellis. “For results that could not be reproduced, however, data were not routinely analyzed by investigators blinded to the experimental versus control groups.”

Good quality preclinical research needs to use the same precautions to avoid bias that well-designed clinical studies use. Preclinical studies should include positive and negative controls, and investigators need to be blinded. Begley and Ellis also recommend that key experiments be repeated by different investigators in the same lab whenever possible and that the final publication reflect all results.

“Journal editors, reviewers and grant-review committees often look for a scientific finding that is simple, clear and complete – a ‘perfect’ story,” say Begley and Ellis. “It is therefore tempting for investigators to submit selected data sets for publication, or even to massage data to fit the underlying hypothesis.” Journal editors, funding agencies, conference organizers, and reviewers need to value well-designed studies even if the results are inconclusive or negative. And readers need to check the quality of a study’s design before being impressed by its groundbreaking discovery.

Begley CG, Ellis LM. Raise standards for preclinical cancer research. Nature. March 29, 2012; 482;531–534. Available at www.nature.com/nature/journal/v483/n7391/full/483531a.html. Accessed June 25, 2015.

Early Palliative Care

Palliative care is often considered end-of-life care, but recent studies are shifting the definition to “specialized medical care … that focuses on relief from symptoms, pain, and psychological distress associated with serious illness,” according to Lynn Howie and Jeffrey Peppercorn. Using palliative care early in the treatment of advanced cancer instead of waiting until death nears provides several benefits for patients, according to their 2013 review article. People with advanced cancer often experience pain, dyspnea, nausea, fatigue, and other symptoms that negatively affect mood and quality of life. Focusing on symptom management during the treatment stage improves patient satisfaction and reduces anxiety and depression. In addition, early palliative care initiates discussions about patients’ goals and preferences so that the information can be incorporated into their care. Contrary to expectations, supplementing active treatment with palliative care appears to reduce overall health costs. Randomized studies have shown that patients receiving early palliative care have fewer emergency room visits and spend fewer days in the hospital.

In addition to improving quality of life and mood, early palliative care increased survival time in a 2010 randomized study led by Jennifer S. Temel, MD. The study randomly assigned 151 patients with newly diagnosed metastatic non-small-cell lung cancer to receive standard care or standard care with palliative care. All treatment was provided at a single medical center, Massachusetts General Hospital (Boston). “Despite the fact that fewer patients in the early palliative care group than in the standard care group received aggressive end-of-life care (33% vs. 54%, P=0.05), median survival was longer among patients receiving early palliative care (11.6 months vs. 8.9 months, P=0.02),” say the authors. The study did not have an attention control arm, which would have helped clarify that palliative care, rather than just additional caregiver time and attention, made the difference. Nonetheless, this study prompted the American Society of Clinical Oncology (ASCO) to issue a provisional clinical opinion advising that palliative care be given to newly diagnosed metastatic lung cancer patients.

Howie and Peppercorn point out that the Temel study cannot be generalized to other types of cancers. More research is needed to determine the most effective time to integrate palliative care for cancers with more variable survival times and to identify the components of palliative care that provide the most benefits. The delivery method for palliative care also needs to be investigated. The Temel study had the advantage of providing conventional care and palliative care at the same facility, which facilitated integration. Moreover, all studies in the Howie-Peppercorn review article used palliative care specialists.

Providing similar care in real-world clinical practice is hampered by the limited number of palliative specialists and by reimbursement systems that balk at paying for disease treatment and palliative care at the same time. Given these barriers, some have suggested that oncologists receive communication and symptom management training that enables them to provide early palliative care. “Oncologists with this training may have ongoing discussions with their patients from the diagnosis of metastatic disease which lead to less use of third- and fourth-line therapies which are less effective and may be more toxic, and may ease the transition from cancer-directed therapies to palliative therapies for their patients with advanced illness,” say Howie and Peppercorn. Comparison studies could evaluate the different effects – if any – between receiving palliative care from a specialist and a trained oncologist.

Contrary to expectation, early palliative care that includes realistic discussions about prognosis does not “reduce patient hope,” say Howie and Peppercorn. Rather, it is an opportunity for patients to consider their goals and determine their care preferences before end of life. That opportunity can be empowering.

Howie L, Peppercorn J. Early palliative care in cancer treatment: rationale, evidence and clinical implications. Ther Adv Med Oncol. 2013;5(6):318–323. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3799294/pdf/10.117. Accessed June 24, 2015.

Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. August 19, 2010;363(8):733–742.

Intravenous Vitamin C and Cancer

People with cancer typically have “very low vitamin C reserves,” according to Ron Hunninghake, MD, so low that they develop scurvy. Hunninghake is chief medical officer at the Olive W. Garvey Center for Healing Arts, the clinical division of the Riordan Clinic in Wichita, Kansas. The molecular structure of vitamin C (ascorbic acid) is very similar to glucose, the primary fuel for cancer cells. Cancer cells actively absorb vitamin C, depleting the body’s tissue reserves. Fatigue, listlessness, easy bruising, poor appetite, sleep disturbance, and low pain threshold – all of which are common among cancer patients – are also symptoms of scurvy. High-dose intravenous vitamin C (IVC) reduces pain, improves appetite and sleep, and helps cancer patients better tolerate chemotherapy and radiation treatment.

Intravenous administration of vitamin C is essential for effective treatment in cancer patients. Oral doses cannot raise plasma levels above ≈ 220 µM (micromolar), even with 3-gram doses given 6 times a day. At oral doses over 200 mg, vitamin C absorption decreases and urine excretion increases, according to a review article by Juan Du et al. However, plasma ascorbate reaches pharmacological levels when given intravenously. A 10-gram infusion of vitamin C produces plasma concentrations from 1 to 5 mM (millimolar). These pharmacologic levels have the additional benefit of selectively killing some cancer cells. “If large amounts of vitamin C are presented to cancer cells, large amounts will be absorbed,” Hunninghake writes. At large concentrations, vitamin C interacts with copper and iron located in cancer cells and produces hydrogen peroxide. Eventually, the peroxide reaches a level that kills the cell.

Published clinical evidence that IVC can be an effective cancer treatment is sparse but not nonexistent. A 2006 article presents three case studies (using NCI Best Case Series guidelines) of patients with advanced cancers who received IVC therapy “as their only significant cancer therapy.” A 51-year-old woman experienced complete regression of metastatic renal cancer after receiving IVC therapy (65 grams twice per week) for 10 months. (More than 4 years after treatment, she was diagnosed with small-cell lung carcinoma that did not respond to IVC.) A 49-year-old man with stage 2 (muscle invasive) bladder cancer had the tumor alone removed, leaving the bladder intact, and commenced IVC (30 grams, twice a week, for 3 months; then 30 grams once every 1–2 months for 4 years). Nine years after diagnosis, he was in good health. A 66-year-old woman with stage III diffuse large B-cell lymphoma agreed to 5 weeks of local radiation therapy along with IVC therapy (15 grams, twice per week for 2 months; once or twice a week for seven months; then once every 2–3 months for about a year). Ten years after diagnosis, she was in good health. Sebastian J. Padayatty and coauthors state, “Although they do not provide grounds for advocating intravenous vitamin C therapy as a cancer treatment, these cases increase the clinical plausibility of the notion that vitamin C administered intravenously might have effects on cancer under certain circumstances.”

More recently, Jeanne Drisko, MD, and Qi Chen, PhD, have been conducting in-depth research on IVC use as a cancer treatment, according to an August/September 2014 Townsend Letter article (available online). Their small 2014 clinical study involving 27 women with advanced ovarian cancer indicated that high-dose IVC could reduce chemotherapy’s toxic effects while increasing the treatment’s effectiveness. The study also showed a trend of delayed cancer progression among women receiving IVC. Drisko and Chen are planning to conduct larger clinical population-based studies to track tumor response and clinical outcomes.

Although high-dose IVC is considered safe for most people, there are some contraindications. Some people with glucose-6-phosphate dehydrogenase deficiency have developed hemolytic anemia after receiving high doses of C. High-dose C may also increase iron absorption, making it unwise for people with systemic iron overload. High-dose IVC is not recommended for people with renal insufficiency or who are undergoing dialysis because ascorbic acid is metabolized to oxalate. Acute oxalate nephropathy has been reported.

For patients can to tolerate it, Hunninghake views IVC as a valuable adjunctive cancer treatment. He says, “IVC can help cancer patients withstand the effects of their traditional therapies, heal faster, be more resilient to infection, develop a better appetite, and remain more active overall. These things promote a better response to their cancer therapy.”

Du J, Cullen JJ, Buettner GR. Ascorbic acid: Chemistry, biology and the treatment of cancer. Biochim Biophys Acta. 2012;1826:443-457. Available at www.ncbi.nlm.nih.gov/pubmed/22728050. Accessed June 24, 2015.

Faass N. Intravenous ascorbate in the treatment of ovarian cancer: the work of Jeanne Drisko, MD and Qi Chen, PhD. Townsend Lett. August/September 2014;373/373:44–49.

Hunninghake R. Intravenous vitamin C and cancer [online article]. Orthomolecular.org. http://www.orthomolecular.org/library/ivccancerpt.shtml. Accessed June 24, 2015.

Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer J, Levine M. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ. March 28, 2006;174(7):937–942. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC1405876/pdf/20060328s00017p937.pdf. Accessed June 24, 2015.

Nigella Sativa (Black cumin)

Nigella sativa (black cumin or black seed) is a spice revered for its medicinal properties by Ayurvedic, Chinese, and Unani (Arabian/Islamic) medicine practitioners. Although Nigella sativa is unfamiliar to most Westerners, Muslims consider it one of nature’s greatest medicines. The seeds and their oil have been used traditionally for thousands of years to treat diarrhea, skin disorders, high blood pressure, liver disorders, infections, digestive complaints, diabetes, and cancers. Modern research indicates that the seed has antioxidant, anti-inflammatory, immunomodulatory, and analgesic properties among its pharmacological effects, according to a 2013 review article by Aftab Ahmad and colleagues. Thymoquinone (TQ) appears to be the main source of the seed’s biological effects. It constitutes over one-third of the seed’s active compounds. Thymoquinone has antioxidant, antimutagenic, and anticancer properties, according to in vitroand animal research.

Although N. sativa has a long traditional history as an anticancer treatment, modern research is just beginning. In vitrostudies show that N. sativa extracts inhibit numerous cancer cell lines by inducing cell death in some and slowing proliferation in others, according to a 2011 review by Md. Asaduzzaman Khan et al. Animal studies indicate that N. sativa oil protects against cancer formation. Oral administration of N. sativa oil inhibited tumor formation in rats exposed to five different carcinogens, according to Ahmad et al. I was unable to find any human clinical studies at this time.

Toxicology studies indicate that oral use of N. sativa seeds, oil, and TQ is safe. The only caveat is that the botanical may affect the pharmacological effect of coadministered drugs. N. sativa extracts inhibit cDNA-expressed human cytochrome P-450-mediated metabolism.

Ahmad A, Husain A, Mujeeb M, et al. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac J Trop Biomed. 2013;3(5):337–352. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3642442/pdf. Accessed June 24, 2015.

Khan MA, Chen H-c, Tania M, Zhang D-Z. Anticancer activities of Nigella sativa (black cumin). Afr J Tradit Complement Altern Med. 2011;8(5):226–232. Available at www.ncbi.nlm.nih.gov/pubmed/22754079. Accessed June 24, 2015.

Radical Remissions

Oncology researchers estimate that one in 65,000 cancer patients experience a spontaneous remission. Psychotherapist-researcher Kelly Turner, PhD, believes that this estimate is too low. Upon learning that no one was studying these anomalies, Turner decided to pursue a doctorate and do the research herself in the belief that these patients hold important clues about healing, specifically about healing from cancer. She visited 10 countries and interviewed 50 holistic healers and 20 radical remission cancer survivors for her dissertation. After obtaining her doctorate, Turner founded the Radical Remission Project to continue researching unexpected cancer remissions that occur after Western medicine has failed or without the use of any Western medicine. During an interview on May 21, 2015, Turner reported documenting 1000 cases of radical remission so far. She chose “radical” instead of “spontaneous” because “spontaneous” connotes a lack of effort or due to no external cause, a connotation that she finds inaccurate.

Although patient diagnoses differ, Turner has observed nine commonalities in those who experienced radical remission. She emphasizes that these factors are just preliminary observations, not conclusive causes or guarantees. Although their journeys to health varied in details, all of the patients took active control of their health and followed their intuition and hunches. “Radical remission survivors listen to the voices in their heads that whisper, ‘Your job is killing you,’ ‘Move your body,’ or, ‘Look for other options,’” she writes. “These gut feelings come from the oldest parts of our brains – parts that we all have but rarely use, because we no longer need to predict hurricanes or know when a tiger is lurking.” Many patients made dietary changes such as avoiding refined sugar and processed foods and increasing consumption of fresh, organic vegetables and fruits. Some patients found herbs and supplements helpful, even necessary for complete healing. Protocols vary, according to individual need.

To Turner’s surprise, the remaining five factors were psychoemotional rather than physical. For some, releasing suppressed emotions was the primary change needed to recover their health. “Even happiness, when held onto, quickly turns into nostalgia for the past, as opposed to joy for the present,” Turner writes. People who experienced radical remission also consciously fostered positive emotions each day – even for 5 minutes – by appreciating the sunrise, petting their cat, or engaging in other activities that brought a smile to their faces. They also welcomed the love and support offered by friends, family, and pets. A daily meditative or spiritual practice that produced a deep, peaceful rest and recharged their energy was another factor. The final commonality was having a strong purpose or reasons for living. Turner discusses these points in greater detail in her book Radical Remission: Surviving Cancer Against All Odds.

Turner says that ignoring these remission cases is “scientifically irresponsible.” She believes that they can tell us a lot about the nature of healing.

Graedon J, Graedon T. Show 955: Surviving cancer against all odds – Dr. Kelly Turner, PhD [radio interview)]. People’s Pharmacy. May 21, 2015.

Turner K. 10 Things I learned about living from studying people who almost died [online article]. mindbodygreen. June 12, 2014. http://www.mindbodygreen.com/0-14013/10-things-i-learned-about-living-from-studying-people-who-almost-died.html. Accessed June 24, 2015.