Nutritional%20Supplements%20That%20Support%20Cancer%20Chemotherapy

1
Nutritional Supplements That SupportCancer
Chemotherapy

• Leo Galland, M.D., F.A.C.P.
• Foundation for
• Integrated Medicine

2
General Overview

• About 1000 drugs and fixed-drug combinations used
  in the U.S.
• Almost 400 may deplete specific nutrients.
• Over 400 may interact with food or food
  components.
• Over 300 have been shown to interact with dietary
  supplements, with adverse and beneficial
  interactions equally common.

3
Types of Interactions

• Pharmacodynamic two substances exhibit
  pharmacologic actions that reinforce or interfere
  with each others actions.
• Pharmacokinetic the absorption, distribution,
  excretion or enzymatic transformation of one
  substance is altered by another. Most adverse
  interactions are of this type.

4
Pharmacokinetic Mechanisms

• Alteration of gastrointestinal or urinary pH.
• Stimulation, induction or inhibition of enzymes
  involved in biotransformation or transport of
  drugs or nutrients .
• Displacement of a drug from binding to plasma
  proteins.
• Alteration of drug solubility.

5
Effects of Interactions

• Nutrient depletion Individual nutrients may have
  their dietary requirement increased by specific
  drugs (or supplements).
• Adverse A specific supplement may undesirably
  decrease or increase the effect of a drug or
  supplement being taken.
• Beneficial Drugs (or supplements) may have their
  actions enhanced or side effects diminished by
  specific supplements.

6
Drug-Induced Nutrient Depletion

• Almost half the drugs used in clinical practice
  have documented nutrient depleting effects.
• Co-enzyme Q10, folic acid, B2, B6, Mg, Zn are
  nutrients most likely to be depleted.
• Mechanisms include impaired absorption or
  bioactivation increased excretion, nausea,
  anorexia or diarrhea (common side effects of
  cancer therapies).

7
Anthracyclines Deplete CoQ10

• Doxorubicin interferes with mitochondrial CoQ
  synthesis, inhibiting succinoxidase and
  NADH-oxidase, contributing to cardiotoxicity.
• CoQ depletion impairs mitochondrial function,
  raising the serum lactate/pyruvate ratio.
• Serum CoQ10 is increased by doxorubicin, due to
  its release from necrotic cardiac tissue.

8
Doxorubicin Plus CoQLaboratory Studies

• CoQ at 1/3 doxorubicin dose prevents
  mitochondrial enzyme inhibition in vitro.
• Rodents CoQ decreases several types of
  doxorubicin toxicity and improves survival.
• No pharmacokinetic interaction.
• Mice CoQ did not impair doxorubicin efficacy
  against Dunn sarcoma.

9
Anthracyclines Plus CoQ10Human Studies

• CoQ 50-90 mg/d prevented ECG changes associated
  with doxorubicin cardiotoxicity
• In patients on doxorubicin 50 mg, 5-FU and
  cytoxan, Co Q 90 mg/day, prevented tachycardia
  and cardiac dilation (vs placebo)
• Lymphoma Co Q 1 mg/kg i.v. for 4 days decreased
  diarrhea, stomatitis and cardiotoxicity with no
  effect on remission rate or mortality.

10
Anthracyclines Plus Carnitine

• Use of L-carnitine or propionyl-L-carnitine
  produced an additive or superior protective
  effect to that of CoQ alone.
• Carnitine administration does not interfere with
  doxorubicin's anti-tumor effect.

11
Anthracyclines Deplete Riboflavin

• Doxorubicin increases riboflavin excretion and
  also blocks FAD synthesis.
• Erythrocyte glutathione reductase (EGR) activity
  measures this effect.
• Providing adequate dietary riboflavin to prevent
  deficiency may decrease doxorubicin toxicity.

12
Doxorubicin Plus Vitamin CLaboratory Studies

• Vit C prolongs lifespan of leukemic mice and
  guinea pigs receiving doxorubicin.
• In vitro, vit C enhances doxorubicin cytotoxicty
  by reducing the Fe-doxorubicin complex that forms
  in cells, increasing peroxidation.

13
Anthracyclines Plus DHA

• Rats DHA from algae increases the sensitivity of
  mammary tumors to epirubicin (and to
  radiotherapy).
• DHA pretreatment decreases tumor vascularity.
• Effects of DHA are reversed by vitamin E in a
  dose-dependent fashion.

14
Anthracyclines Plus L-theanine(5-N-ethyl
glutamine)

• Rodents L-Theanine, a unique amino acid found in
  green tea, enhances the efficacy and decreases
  toxicity of doxorubicin and idarubicin.
• Theanine inhibits glutamate-mediated doxorubicin
  efflux, only in cancer cells.
• In normal cells, theanine increases intracellular
  glutamate and glutathione levels and does not
  increase doxorubicin concentration.

15
CISPLATIN DEPLETES Mg, K, Se, VIT E

• Inhibits Mg transport proteins ? renal Mg
  wasting, depletes muscle Mg,K before serum.
• 75 incidence of hypomagnesemia, 50 lasts gt3 yr.
  Sensory neuropathy correlates with S-Mg.
• Reduces circulating vit E and numerous
  antioxidants, correlates with neurotoxicity.
• Se in blood decreases progressively with each
  infusion in patients with testicular cancer.

16
Cisplatin ToxicityProtective Supplements

• Bismuth 150 mg/kg/day X 10 days
• Ginkgo biloba 100 mg/kg single dose
• Glutathione 5 gm i.v. prior to infusion
• MgSO4 3 gm i.v./ Mg 160 mg tid
• N-acetyl cysteine 8 gm/day
• Selenium 4000 mcg/day X 8 days
• Vitamin C 50-200 mg/kg i.v. single dose
• Vitamin E 300 IU/day till 3 months post

17
Magnesium Diminshes Cisplatin Toxicity

• Combined oral and i.v. Mg reduced nephrotoxicity
  in patients with testicular cancer.
• Prophylactic Mg is more effective than attempted
  correction of a deficit.
• Mg does not interfere with efficacy

18
Cisplatin Plus Antioxidants

• D-alpha-tocopherol, 300 IU/d reduced
  neurotoxicity when given from start of chemoRx
  until 3 months post.
• Vits E, C and Se decreased ototoxicity, only in
  patients with increased blood levels of all 3.
• D-alpha-tocopherol enhances cisplatin's
  anti-tumor effect in rodents by increasing drug
  concentration in tumor without increasing its
  concentration in healthy tissue.

19
Cisplatin Plus Vitamin CLaboratory Studies

• Vit C enhances cisplatin antineoplastic
  cytotoxicity in vitro and in vivo
• Vitamin C protects against cisplatin-induced
  oxidant stress of normal tissues
• Rats Vit C (50-200 mg/kg) 10 minutes before
  cisplatin decreased nephrotoxicity and markers of
  systemic oxidant stress.

20
Cisplatin Plus SeleniumRodent Studies

• Se 2 mg/kg (sodium selenite) p.o. prior to
  cisplatin (but not post) prevented nephrotoxicity
• Sodium selenite did not interfere with the
  therapeutic effect of cisplatin against mouse
  breast or plasma cell cancers in vivo.
• Se 1.5 mg/kg with cisplatin prevented cisplatin
  resistance and enhanced efficacy in mice with
  human ovarian cancer explants

21
Cisplatin Plus GlutathioneClinical Trials

• i.v. GSH (5 g) just prior to cisplatin, reduces
  nephrotoxicity without impairing efficacy
  (ovarian cancer).
• GSH reduced neurotoxicity in patients with
  advanced gastric cancer. Dose 3 g pre-cisplatin
  600 mg i.m. qd X 4 days.

22
Cisplatin Plus Gingko BilobaRodent Studies

• Ginkgo biloba extract (GBE, 100 mg/kg) prevent
  ototoxicity in mice and rats.
• GBE as a single dose, 90 minutes before cisplatin
  infusion, does not impair anti-tumor efficacy.

23
Bismuth and CisplatinMetallothionein Induction

• Bismuth 150 mg/kg for 10 days prevents
  nephrotoxicity in humans by inducing
  metallothionein in healthy cells, not cancer
  cells.
• Poor solubility of bismuth is overcome by
  dissolving it in a citric acid solution.

24
N-acetylcysteine and Cisplatin Diverse
Protective Effects

• NAC protects renal cells against cisplatin by
  inhibiting GGT, needed for nephrotoxic effects.
• Case report reversal of renal failure with NAC
  140 mg/kg followed by 70 mg/kg q4h X 4 days
• NAC 8 g/d did not block cisplatin/ifosfamide Rx
• NAC enhances cisplatin cytoxocity for prostate ca
  cells by antagonizing cisplatin-induced increase
  in NFkB activity.

25
NAC and Ifosfamide

• NAC (4-8 g/day) protects against the urological
  side effects of ifosfamide, especially
  hemorrhagic cystitis, permitting the use of
  higher doses of ifosfamide.
• NAC shows less protective effect than Mesna.

26
Melatonin and Advanced Solid Tumors

• Melatonin (20 mg HS) improved survival and
  reduced side effects of patients with non-small
  cell lung cancer being treated with cisplatin and
  etoposide, with doubling of one-year survival and
  reduction of myelosuppression, neuropathy and
  cachexia.
• Appeared to enhance effectiveness of low-dose
  irinotecan in patients with colorectal cancer.

27
Melatonin/Tamoxifen

• Melatonin, 20 mg/day hs, with tamoxifen, 20
  mg/day at noon, improved clinical status in 28
  of patients with metastatic breast cancer
  unresponsive to tamoxifen alone.
• Melatonin augments sensitivity of breast cancer
  cells to tamoxifen in tissue culture
• Melatonin interferes with activation of the
  estrogen receptor by estradiol and also inhibits
  aromatase

28
GAMMA-LINOLENIC ACID/ TAMOXIFEN

• GLA (2800 mg/d) speeded the response to tamoxifen
  (20 mg/d) as primary treatment for postmenopausal
  breast ca.
• GLA down-regulates estrogen receptor expression
  in human breast cancer xenografts in mice and in
  tissue culture.

29
PSK from Coriolus versicolorImmune Enhancing
Adjuvant

• PSK 1 g tid for up to 3 y enhances outcome for
  advanced solid tumors (over 50 clinical trials).
• Various biomarkers predict response
• Humans PSK enhances PMN number and function,
  raises IgG and IgM levels
• Mice PSK enhances TH1 function, increases IL-12,
  and reverses TH2 dominance.

30
Glutamine Broad Protection Against
Antineoplastic Side Effects

• Stomatitis reduced by 4 g bid or 2 g qid
  glutamine powder, swish swallow
• Esophageal ca 10 g tid ameliorated lymphopenia,
  enhanced lymphocyte mitogen stimulation and
  diminished increase in intestinal permeability
  due to radiochemotherapy.
• Glutamine increases GSH in normal cells and
  reduces GSH in cancer cells.

31
5-FU Plus Glutamine

• Oral glutamine, 18 g/day, reduced diarrhea,
  malabsorption and increased small intestinal
  permeability in patients with colorectal cancer.
• Glutamine did not prevent 5-FU-induced stomatitis.

32
MTX Plus Glutamine

• Rats oral glutamine 1 g/kg/d increases MTX
  uptake by breast cancer and fibrosarcoma cells,
  enhancing efficacy and decreasing toxicity.
• Humans Glutamine did not interfere with
  therapeutic effects of MTX in inflammatory breast
  cancer.

33
Paclitaxel Plus Glutamine

• Glutamine 4 g q4h or 10 g tid reduce muscle and
  joint pain, oral mucositis and peripheral
  neuropathy in most studies.
• Oral glutamine supplementation may enhance the
  therapeutic index by protecting normal tissues
  from, and sensitizing tumor cells to chemotherapy
  and radiation-related injury.

34
Prevention of chemotherapy and radiation toxicity
with glutamine. Savarese et al, Cancer Treat
Reviews 2003 29501-13

• The available evidence suggests that glutamine
  supplementation may decrease the incidence and/or
  severity of chemotherapy-associated mucositis,
  irinotecan-associated diarrhea,
  paclitaxel-induced neuropathy, hepatic
  veno-occlusive disease in the setting of high
  dose chemotherapy and stem cell transplantation,
  and the cardiotoxicity that accompanies
  anthracycline use. Oral glutamine supplementation
  may enhance the therapeutic index by protecting
  normal tissues from, and sensitizing tumor cells
  to chemotherapy and radiation-related injury.

35
Vitamin B6 vsPalmar-Plantar Erythrodysesthesia

• Vitamin B6 (50 mg t.i.d.) reverses symptoms of
  the palmar-plantar erythrodysesthesia syndrome
  (PPE) in patients receiving docetaxel and 5-FU.
• This syndrome may occur with many other
  antineoplastic agents, although vitamin B6
  therapy has not been tested for its prevention.

36
ABC Transport Proteins

• Eject xenobiotics from cells and cause backflow
  of some drugs from intestinal mucosa into the
  lumen.
• Produce multi-drug resistance to cancer
  chemotherapy.
• Inhibited by piperine, milk thistle, ginseng,
  curcumin, quercetin.
• Stimulated by chronic use of St. Johns wort.

37
Vitamin K InducesCell Differentiation

• HCC Vit K2 15 mg tid reduces incidence by 80 in
  women with cirrhosis
• HCC Vit K2 15 mg tid prolongs 3-year survival by
  35 following resection.
• MDS Vit K2 induces differentiation of leukemic
  cell lines and blast apoptosis and improves anemia

38
Conclusions

• Adverse interactions have received extensive
  press coverage.
• Beneficial drug-supplement interactions are at
  least as important and permit creative
  nutritional therapies.
• By decreasing side effects of antineoplastic
  drugs, properly used supplements may prevent
  therapeutic failure due to under-dosing