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Хирургическая онкология. Регионарная химиотерапия.

Vitamin C kills tumor cells with hard-to-treat mutation

Maybe Linus Pauling was on to something after all. Decades ago the Nobel Prize–winning chemist was relegated to the fringes of medicine after championing the idea that vitamin C could combat a host of illnesses, including cancer. Now, a study published online today in Science reports that vitamin C can kill tumor cells that carry a common cancer-causing mutation andin mice—can curb the growth of tumors with the mutation.

If the findings hold up in people, researchers may have found a way to treat a large swath of tumors that has lacked effective drugs. "This [could] be one answer to the question everybody's striving for," says molecular biologist Channing Der of the University of North Carolina, Chapel Hill, one of many researchers trying to target cancers with the mutation. The study is also gratifying for the handful of researchers pursuing vitamin C, or ascorbic acid, as a cancer drug. "I'm encouraged. Maybe people will finally pay attention," says vitamin C researcher Mark Levine of the National Institute of Diabetes and Digestive and Kidney Diseases.

 In 1971, Pauling began collaborating with a Scottish physician who had reported success treating cancer patients with vitamin C. But the failure of two clinical trials of vitamin C pills, conducted in the late 1970s and early 1980s at the Mayo Clinic in Rochester, Minnesota, dampened enthusiasm for Pauling’s idea. Studies by Levine’s group later suggested that the vitamin must be given intravenously to reach doses high enough to kill cancer cells. A few small trials in the past 5 yearsfor pancreatic and ovarian cancerhinted that IV vitamin C treatment combined with chemotherapy can extend cancer survival. But doubters were not swayed. "The atmosphere was poisoned" by the earlier failures, Levine says.

A few years ago, Jihye Yun, then a graduate student at Johns Hopkins University in Baltimore, Maryland, found that colon cancer cells whose growth is driven by mutations in the gene KRAS or a less commonly mutated gene, BRAF, make unusually large amounts of a protein that transports glucose across the cell membrane. The transporter, GLUT1, supplies the cells with the high levels of glucose they need to survive. GLUT1 also transports the oxidized form of vitamin C, dehydroascorbic acid (DHA), into the cell, bad news for cancer cells, because Yun found that DHA can deplete a cell’s supply of a chemical that sops up free radicals. Because free radicals can harm a cell in various ways, the finding suggested “a vulnerability” if the cells were flooded with DHA, says Lewis Cantley at Weill Cornell Medicine in New York City, where Yun is now a postdoc.

Cantley’s lab and collaborators found that large doses of vitamin C did indeed kill cultured colon cancer cells with BRAF or KRAS mutations by raising free radical levels, which in turn inactivate an enzyme needed to metabolize glucose, depriving the cells of energy. Then they gave daily high dose injectionsequivalent to a person eating 300 orangesto mice engineered to develop KRAS-driven colon tumors. The mice developed fewer and smaller colon tumors compared with control mice.

Cantley hopes to soon start clinical trials that will select cancer patients based on KRAS or BRAF mutations and possibly GLUT1 status. His group’s new study "tells you who should get the drug and who shouldn't," he says. Cancer geneticist Bert Vogelstein of Johns Hopkins University, in whose lab Yun noticed the GLUT1 connection, is excited about vitamin C therapy, not only as a possible treatment for KRAS-mutated colon tumors, which make up about 40% of all colon cancers, but also for pancreatic cancer, a typically lethal cancer driven by KRAS. “No KRAS-targeted therapeutics have emerged despite decades of effort and hundreds of millions of dollars [spent] by both industry and academia,” Vogelstein says. 

Others caution that the effects seen in mice may not hold up in humans. But because high dose vitamin C is already known to be safe, says cancer researcher Vuk Stambolic of the University of Toronto in Canada, oncologists “can quickly move forward in the clinic."

One drawback is that patients will have to come into a clinic for vitamin C infusions, ideally every few days for months, because vitamin C seems to take that long to kill cancer cells, Levine notes. But Cantley says it may be possible to make an oral formulation that reaches high doses in the bloodwhich may be one way to get companies interested in sponsoring trials.


 * Vitamin C, also known as ascorbic acid, is a water-soluble vitamin
   <http://lpi.oregonstate.edu/mic/glossary#vitamin>. Unlike most mammals and other animals, humans
   do not have the ability to make ascorbic acid and must obtain vitamin C from the diet.
 * Inside our bodies, vitamin C functions as an essential cofactor
   <http://lpi.oregonstate.edu/mic/glossary#cofactor> in numerous enzymatic
   <http://lpi.oregonstate.edu/mic/glossary#enzyme> reactions, e.g., in the biosynthesis of
   collagen <http://lpi.oregonstate.edu/mic/glossary#collagen>, carnitine
   <http://lpi.oregonstate.edu/mic/glossary#carnitine>, and catecholamines
   <http://lpi.oregonstate.edu/mic/glossary#catecholamine>, and as a potent antioxidant
   <http://lpi.oregonstate.edu/mic/glossary#antioxidant>. //
 * Prospective cohort studies <http://lpi.oregonstate.edu/mic/glossary#prospective-cohort-study>
   indicate that higher intakes of vitamin C from either diet or supplements are associated with a
   reduced risk <http://lpi.oregonstate.edu/mic/glossary#risk> of cardiovascular disease
   <http://lpi.oregonstate.edu/mic/glossary#cardiovascular-disease> (CVD), including coronary heart
   disease <http://lpi.oregonstate.edu/mic/glossary#coronary-heart-disease> and stroke
 * Observational <http://lpi.oregonstate.edu/mic/glossary#observational-study> prospective cohort
   studies report no or modest inverse associations between vitamin C intake and the risk of
   developing a given type of cancer <http://lpi.oregonstate.edu/mic/glossary#cancer>. Randomized
   controlled trials <http://lpi.oregonstate.edu/mic/glossary#randomized-controlled-trial> have
   shown no effect of vitamin C supplementation on cancer outcomes.
 * Prospective cohort studies indicate that higher blood levels of vitamin C are associated with
   lower risk of death from all-causes, cancer, and CVD.
 * Pharmacological doses <http://lpi.oregonstate.edu/mic/glossary#pharmacologic-dose> of vitamin C
   administered intravenously <http://lpi.oregonstate.edu/mic/glossary#intravenous> are generally
   safe and well tolerated in cancer patients. The potential for intravenous ascorbic acid as an
   adjunct <http://lpi.oregonstate.edu/mic/glossary#adjunct> to cancer therapies is currently under
   investigation in phase II clinical trials
   <http://lpi.oregonstate.edu/mic/glossary#phase-II-clinical-trial>. //
 * Overall, there is evidence that regular use of vitamin C supplements shortens the duration of
   the common cold, but the effect in cold treatment may be limited. //
 * Vitamin C supplements are available in many forms, but there is little scientific evidence that
   any one form is better absorbed or more effective than another.
 * There is no scientific evidence that large amounts of vitamin C (up to 10 grams/day in adults)
   exert any adverse or toxic effects. An upper level of 2 grams/day is recommended in order to
   prevent some adults from experiencing diarrhea and gastrointestinal
   <http://lpi.oregonstate.edu/mic/glossary#gastrointestinal> disturbances.
 * Supplemental vitamin C increases urinary oxalate levels, but whether an increase in urinary
   oxalate elevates the risk for kidney stones
   <http://lpi.oregonstate.edu/mic/glossary#kidney-stones> is not yet known. Those predisposed for
   kidney stone formation may consider avoiding high-dose (≥1,000 mg/day) vitamin C supplementation. /
   / <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#kidney-stones>


Vitamin C is a potent reducing <http://lpi.oregonstate.edu/mic/glossary#reduction> agent, meaning that it readily donates electrons <http://lpi.oregonstate.edu/mic/glossary#electron> to recipient molecules. Related to this oxidation-reduction (redox <http://lpi.oregonstate.edu/mic/glossary#redox-reaction>) potential, two major functions of vitamin C are as an antioxidant <http://lpi.oregonstate.edu/mic/glossary#antioxidant> and as an enzyme <http://lpi.oregonstate.edu/mic/glossary#enzyme> cofactor <http://lpi.oregonstate.edu/mic/glossary#cofactor> (1, 2) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#references>.

Vitamin C is the primary water-soluble, non-enzymatic antioxidant in plasma <http://lpi.oregonstate.edu/mic/glossary#plasma> and tissues (1, 2) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#references>. Even in small amounts vitamin C can protect indispensable molecules in the body, such as proteins <http://lpi.oregonstate.edu/mic/glossary#protein>, lipids <http://lpi.oregonstate.edu/mic/glossary#lipid> (fats), carbohydrates <http://lpi.oregonstate.edu/mic/glossary#carbohydrate>, and nucleic acids <http://lpi.oregonstate.edu/mic/glossary#nucleic-acid> (DNA <http://lpi.oregonstate.edu/mic/glossary#DNA> and RNA <http://lpi.oregonstate.edu/mic/glossary#RNA>), from damage by free radicals <http://lpi.oregonstate.edu/mic/glossary#free-radical> and reactive oxygen species <http://lpi.oregonstate.edu/mic/glossary#reactive-oxygen-species> (ROS) that are generated during normal metabolism <http://lpi.oregonstate.edu/mic/glossary#metabolism>, by active immune cells, and through exposure to toxins and pollutants (e.g., certain chemotherapy <http://lpi.oregonstate.edu/mic/glossary#chemotherapy> drugs and cigarette smoke). Vitamin C also participates in redox recycling of other important antioxidants; for example, vitamin C is known to regenerate vitamin E <http://lpi.oregonstate.edu/mic/vitamins/vitamin-E> from its oxidized <http://lpi.oregonstate.edu/mic/glossary#oxidation> form (3, 4) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference3>.

Vitamin C’s role as a cofactor is also related to its redox potential. By maintaining enzyme-bound metals in their reduced forms, vitamin C assists mixed-function oxidases in the synthesis <http://lpi.oregonstate.edu/mic/glossary#synthesis> of several critical biomolecules (1, 2) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#references>. Symptoms of vitamin C deficiency, such as poor wound healing and lethargy, result from impairment of these enzymatic reactions and insufficient collagen <http://lpi.oregonstate.edu/mic/glossary#collagen>, carnitine <http://lpi.oregonstate.edu/mic/glossary#carnitine>, and catecholamine <http://lpi.oregonstate.edu/mic/glossary#catecholamine> synthesis (see Deficiency <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#deficiency>). Research also suggests that vitamin C is involved in the metabolism of cholesterol <http://lpi.oregonstate.edu/mic/glossary#cholesterol> to bile acids <http://lpi.oregonstate.edu/mic/glossary#bile-acids>, which may have implications for blood cholesterol levels and the incidence of gallstones <http://lpi.oregonstate.edu/mic/glossary#gallstones> (5) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference5>.

Finally, vitamin C increases the bioavailability <http://lpi.oregonstate.edu/mic/glossary#bioavailability> of iron from foods by enhancing intestinal absorption of non-heme <http://lpi.oregonstate.edu/mic/glossary#heme> iron (1) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#references>

Vitamin C in Cancer

Overall, observational <http://lpi.oregonstate.edu/mic/glossary#observational-study> prospective cohort studies <http://lpi.oregonstate.edu/mic/glossary#prospective-cohort-study> report no or modest inverse associations between vitamin C intake and the risk <http://lpi.oregonstate.edu/mic/glossary#risk> of developing a given type of cancer <http://lpi.oregonstate.edu/mic/glossary#cancer> (3 <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference3>, 36-38) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference36>. Additional detail is provided below for those cancer subtypes with substantial scientific information obtained from prospective cohort studies. Randomized <http://lpi.oregonstate.edu/mic/glossary#randomized-design>, double-blind <http://lpi.oregonstate.edu/mic/glossary#double-blind>, placebo <http://lpi.oregonstate.edu/mic/glossary#placebo>-controlled trials that have tested the effect of vitamin C supplementation (alone or in combination with other antioxidant <http://lpi.oregonstate.edu/mic/glossary#antioxidant> nutrients) on cancer incidence or mortality have shown no effect (39) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference39>.

Breast cancer

Two large, prospective studies found dietary vitamin C intake to be inversely associated with breast cancer incidence in certain subgroups. In the Nurses' Health Study, premenopausal women with a family history of breast cancer who consumed an average of 205 mg/day of vitamin C from foods had a 63% lower risk <http://lpi.oregonstate.edu/mic/glossary#risk> of breast cancer than those who consumed an average of 70 mg/day (40) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference40>. In the Swedish Mammography Cohort, overweight women who consumed an average of 110 mg/day of vitamin C had a 39% lower risk of breast cancer compared to overweight women who consumed an average of 31 mg/day (41) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference41>. More recent prospective cohort studies have found no association between dietary and/or supplemental vitamin C intake and breast cancer (42-44) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference42>.

Stomach cancer

A number of observational studies <http://lpi.oregonstate.edu/mic/glossary#observational-study> have found increased dietary vitamin C intake to be associated with decreased risk <http://lpi.oregonstate.edu/mic/glossary#risk> of stomach cancer <http://lpi.oregonstate.edu/mic/glossary#cancer>, and laboratory experiments indicate that vitamin C inhibits the formation of carcinogenic <http://lpi.oregonstate.edu/mic/glossary#carcinogen> N-nitroso compounds in the stomach (45-47) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference45>. A nested case-control study <http://lpi.oregonstate.edu/mic/glossary#nested-case-control-study> in the EPIC study found an inverse association between plasma <http://lpi.oregonstate.edu/mic/glossary#plasma> vitamin C and gastric <http://lpi.oregonstate.edu/mic/glossary#gastric> cancer incidence in the highest (≥51 μmol/L) versus lowest (<29 μmol/L) quartiles <http://lpi.oregonstate.edu/mic/glossary#quartile> of plasma vitamin C concentration (Odds Ratio <http://lpi.oregonstate.edu/mic/glossary#odds-ratio> (OR): 0.55, 95% CI <http://lpi.oregonstate.edu/mic/glossary#confidence-interval>: 0.31-0.97); no association between dietary vitamin C intake and gastric cancer risk was observed (48) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference48>.

Infection with the bacteria <http://lpi.oregonstate.edu/mic/glossary#bacteria>, /Helicobacter pylori/ (/H. pylori/), is known to increase the risk of stomach cancer and is associated with lower vitamin C content of stomach secretions (49, 50) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference49>. Although two intervention studies <http://lpi.oregonstate.edu/mic/glossary#intervention-trial> did not find a decrease in the occurrence of stomach cancer with vitamin C supplementation (17) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference17>, more recent research suggests that vitamin C supplementation may be a useful addition to standard /H. pylori/ eradication therapy in reducing the risk of gastric cancer (51) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference51>. Because vitamin C can inactivate urease, an enzyme <http://lpi.oregonstate.edu/mic/glossary#enzyme> that facilitates /H. pylori/ survival and colonization of the gastric mucosa <http://lpi.oregonstate.edu/mic/glossary#gastric-mucosa> at low pH <http://lpi.oregonstate.edu/mic/glossary#pH>, vitamin C may be most effective as a prophylactic <http://lpi.oregonstate.edu/mic/glossary#prophylaxis> agent in those without achlorhydria <http://lpi.oregonstate.edu/mic/glossary#achlorhydria> (52) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference52>.

Colon cancer

By pooling data from 13 cohort studies comprising 676,141 participants, it was determined that dietary intake of vitamin C was not associated with colon cancer, while total intake of vitamin C (i.e., from food and supplements) was associated with a modestly reduced risk <http://lpi.oregonstate.edu/mic/glossary#risk> of colon cancer (Relative Risk <http://lpi.oregonstate.edu/mic/glossary#relative-risk> (RR): 0.81, 95% CI <http://lpi.oregonstate.edu/mic/glossary#confidence-interval>: 0.71-0.92, >600 vs. ≤100 mg/day) (53) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference53>. Each of the cohort studies used self-administered food frequency questionnaires <http://lpi.oregonstate.edu/mic/glossary#food-frequency-questionnaire> at baseline to assess vitamin C intake. Although the analysis adjusted for several lifestyle and known risk factors, the authors note that other healthy behaviors and/or folate intake may have confounded <http://lpi.oregonstate.edu/mic/glossary#confounder> the association.

Non-Hodgkin lymphoma (NHL)

A population-based, prospective study, the Iowa Women’s Health Study, collected baseline data on diet and supplement use in 35,159 women (aged 55-69 years) and evaluated the risk <http://lpi.oregonstate.edu/mic/glossary#risk> of developing NHL after 19 years of follow-up (54) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference54>. Overall, an inverse association between fruit and vegetable intake and risk of NHL was observed. Additionally, dietary, but not supplemental, intake of vitamin C and other antioxidant <http://lpi.oregonstate.edu/mic/glossary#antioxidant> nutrients (carotenoids <http://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/carotenoids>, proanthocyanidins, and manganese <http://lpi.oregonstate.edu/mic/minerals/manganese>) was inversely associated with NHL risk, suggesting that the association of NHL with these individual antioxidants may be mediated through food sources. The Women's Health Initiative was a large, multi-center, prospective study that assessed the association between antioxidant nutrient intake and risk of NHL, among other chronic diseases <http://lpi.oregonstate.edu/mic/glossary#chronic-disease>, in 154,363 postmenopausal women (55) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference55>. After 11 years of follow-up, dietary and supplemental vitamin C intake at baseline was inversely associated with diffuse B-cell lymphoma, a subtype of NHL.

Cancer Treatment 

Studies in the 1970s and 1980s conducted by Linus Pauling, Ewan Cameron, and colleagues suggested that very large doses of vitamin C (10 grams/day infused intravenously <http://lpi.oregonstate.edu/mic/glossary#intravenous> for 10 days followed by at least 10 grams/day orally indefinitely) were helpful in increasing the survival time and improving the quality of life of terminal cancer <http://lpi.oregonstate.edu/mic/glossary#cancer> patients (107) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference107>. Controversy surrounding the efficacy of vitamin C in cancer treatment ensued, leading to the recognition that the route of vitamin C administration is critical (6 <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference6>, 108) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference108>. Compared to orally administered vitamin C, intravenous vitamin C can result in 30 to 70-fold higher plasma levels of vitamin C (9) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference9>. The higher plasma levels achieved via intravenous ascorbic acid administration are comparable to those that are toxic to cancer cells in culture. The anticancer mechanism of intravenous vitamin C action is under investigation. It may involve the production of high levels of hydrogen peroxide, selectively toxic to cancer cells (6 <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference6>, 109-111) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference109>, or the deactivation of hypoxia inducible factor, a prosurvival transcription factor <http://lpi.oregonstate.edu/mic/glossary#transcription-factor> that protects cancer cells from various forms of stress (108, 112, 113) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference108>.

Currently, results from controlled clinical trials <http://lpi.oregonstate.edu/mic/glossary#clinical-trial> indicate that intravenous vitamin C is generally safe and well tolerated in cancer patients. Four phase I clinical trials <http://lpi.oregonstate.edu/mic/glossary#phase-I-clinical-trial> in patients with advanced cancer found that intravenous administration of vitamin C at doses up to 1.5 g/kg of body weight and 70-80 g/m^2 was well tolerated and safe in pre-screened patients (114-117) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference114>. A retrospective <http://lpi.oregonstate.edu/mic/glossary#retrospective-study> analysis of breast cancer patients reported that complementary intravenous ascorbic acid treatment reduced quality-of-life related side effects of chemotherapy <http://lpi.oregonstate.edu/mic/glossary#chemotherapy> (118) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference118>. A phase I study in nine patients with metastatic pancreatic cancer showed that millimolar levels of plasma ascorbic acid could be reached safely when administered in conjunction with the cancer chemotherapy drugs, gemcitabine and erlotinib (116) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference116>.

In a pilot study <http://lpi.oregonstate.edu/mic/glossary#pilot-study> performed in 15 patients with refractory myelodisplastic syndrome or acute myeloid leukemia, an alternating ascorbic acid depletion/intravenous repletion protocol was safe and elicited a clinical response in a subset of nine patients (119) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference119>. Retrospective /in vitro/ <http://lpi.oregonstate.edu/mic/glossary#in-vitro> colony formation assays revealed that patient leukemic cells displayed variable sensitivity to ascorbic acid treatment: leukemic cells from seven out of the nine patients who experienced a significant clinical benefit were sensitive to ascorbic acid in vitro (i.e., "responders"); the leukemic cells from the remaining six patients were not sensitive to ascorbic acid (i.e., "non-responders"). Thus, /in vitro/ ascorbic acid sensitivity assays may provide predictive value for the clinical response to intravenous vitamin C treatment. The mechanisms underlying differential sensitivity to ascorbic acid are under investigation. /In vitro/ experiments performed using 11 different cancer cell lines demonstrated that sensitivity to ascorbic acid correlated with the expression of catalase, an enzyme involved in the decomposition of hydrogen peroxide (120) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference120>. Approximately half of the cell lines tested were resistant to ascorbic acid cytotoxicity, a response associated with high levels of catalase activity. Sensitivity to ascorbic acid may also be determined by the expression of sodium-dependent vitamin C transporter-2 (SVCT-2), which transports ascorbic acid into cells (121) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference121>. Higher SVCT-2 levels were associated with enhanced sensitivity to L-ascorbic acid in nine different breast cancer cell lines. Moreover, SVCT-2 was significantly expressed in 20 breast cancer tissue samples, but weakly expressed in normal tissues.

These pilot and phase I study results motivate larger, longer-duration phase II clinical trials <http://lpi.oregonstate.edu/mic/glossary#phase-ii-clinical-trial> that test the efficacy of intravenous ascorbic acid in disease progression and overall survival. Such phase II clinical trials are currently under way (122) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference122>. Because different cancer subtypes may be recalcitrant or require different doses of intravenous vitamin C, phase II trials are necessary before use of intravenous vitamin C as an anti-tumor agent can be fully realized (123) <http://lpi.oregonstate.edu/mic/vitamins/vitamin-C#reference123>. For information about the use of high-dose intravenous vitamin C as an adjunct <http://lpi.oregonstate.edu/mic/glossary#adjunct> in cancer treatment, visit The University of Kansas Medical Center Program in Integrative Medicine website <http://www.kumc.edu/school-of-medicine/integrative-medicine.html>.

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