Transcript Interactions in Clinical Practice: Drug

Nutritional Supplements
That Support
Cancer Chemotherapy
Leo Galland, M.D., F.A.C.P.
Foundation for
Integrated Medicine
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.
Types of Interactions
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Pharmacodynamic: two substances
exhibit pharmacologic actions that
reinforce or interfere with each other’s
actions.
Pharmacokinetic: the absorption,
distribution, excretion or enzymatic
transformation of one substance is altered
by another. Most adverse interactions are
of this type.
Pharmacokinetic Mechanisms
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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.
Effects of Interactions
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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.
Drug-Induced
Nutrient Depletion
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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).
Anthracyclines Deplete CoQ10
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Doxorubicin interferes with mitochondrial CoQ
synthesis, inhibiting succinoxidase and NADHoxidase, contributing to cardiotoxicity.
CoQ depletion impairs mitochondrial function,
raising the serum lactate/pyruvate ratio.
Serum CoQ10 is increased by doxorubicin, due
to it’s release from necrotic cardiac tissue.
Doxorubicin Plus CoQ:
Laboratory Studies
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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.
Anthracyclines Plus CoQ10:
Human Studies
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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.
Anthracyclines Plus Carnitine
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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.
Anthracyclines Deplete Riboflavin
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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.
Doxorubicin Plus Vitamin C:
Laboratory Studies
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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.
Anthracyclines Plus DHA
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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.
Anthracyclines Plus L-theanine
(5-N-ethyl glutamine)
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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.
CISPLATIN DEPLETES
Mg, K, Se, VIT E
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Inhibits Mg transport proteins  renal Mg
wasting, depletes muscle Mg,K before serum.
75% incidence of hypomagnesemia, 50% lasts
>3 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.
Cisplatin Toxicity:
Protective Supplements
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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
Magnesium Diminshes
Cisplatin Toxicity
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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
Cisplatin Plus Antioxidants
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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 antitumor effect in rodents by increasing drug
concentration in tumor without increasing its
concentration in healthy tissue.
Cisplatin Plus Vitamin C:
Laboratory Studies
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Vit C enhances cisplatin antineoplastic
cytotoxicity in vitro and in vivo
Vitamin C protects against cisplatininduced oxidant stress of normal tissues
Rats: Vit C (50-200 mg/kg) 10 minutes
before cisplatin decreased nephrotoxicity
and markers of systemic oxidant stress.
Cisplatin Plus Selenium:
Rodent Studies
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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
Cisplatin Plus Glutathione:
Clinical Trials
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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 precisplatin + 600 mg i.m. qd X 4 days.
Cisplatin Plus Gingko Biloba:
Rodent Studies
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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 antitumor efficacy.
Bismuth and Cisplatin:
Metallothionein Induction
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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.
N-acetylcysteine and Cisplatin:
Diverse Protective Effects
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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.
NAC and Ifosfamide
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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.
Melatonin and
Advanced Solid Tumors
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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.
Melatonin/Tamoxifen
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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
GAMMA-LINOLENIC ACID/
TAMOXIFEN
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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.
PSK from Coriolus versicolor:
Immune Enhancing Adjuvant
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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 IL12, and reverses TH2 dominance.
Glutamine: Broad Protection
Against Antineoplastic Side Effects
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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.
5-FU Plus Glutamine
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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.
MTX Plus Glutamine
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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.
Paclitaxel Plus Glutamine
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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.
Prevention of chemotherapy and radiation toxicity
with glutamine. Savarese et al,
Cancer Treat Reviews 2003; 29:501-13
“ 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.”
Vitamin B6 vs
Palmar-Plantar Erythrodysesthesia
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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.
ABC Transport Proteins
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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. John’s wort.
Vitamin K Induces
Cell Differentiation
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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
Conclusions
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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