TheLong-termSurvivalofaPatientWithPancreaticCancerWithMetastasestotheLiverAfterT reatmentWiththeIntravenous -LipoicAcid/Low-DoseNaltrexoneProtocol Burton M.Berkson,Daniel M.Rubin,and Arthur J.Berkson Theauthorsdescribethelong-termsurvivalofapatientwith pancreatic cancer without a ny toxic adverse effects.

Thetreatment regimen includes the intravenous -lipoic acidand low-dose naltrexone (ALA-N) protocol and a healthy lifestyleprogram.Thep atientwastoldbyareputableuniver-sity oncology center in October 2002 that there was littlehope for his survival. Today, January 2006, however, he isback at work , free from symptoms, and without appreciable progression of his malignancy. The integrative protocol de-scribed in this article may have the possibility of ext ending thelifeofapatientwhowouldbecustomarilyconsideredtobe terminal. The author s believe that life scientists will onedaydevelopacureformetastaticpancreaticcan cer,perhaps via gene therapy or another biological platform. But untilsuch proto cols come to market, the ALA-N protocol shouldbe studied and considered, given i ts lack of toxicity at levelsreported.Severalotherpatientsareonthistreatmentprot o-col and appear to be doing well at this time. Keywords:pancreatic cancer; naltrexone; lipoic acid; survival J.A. is a 46-year-old man diagnosed with poorly differ-entiated adenocarcinoma of the pancreas withmetastases to the liver. In early October 2002, J.A.started to feel vague abdominal pains as well as com-plained of symptoms associated with hyperacidity andindigestion. After his symptoms became more pro-nounced,heprese ntedtothelocalemergencydepart-mentwhere,secondarytohiscomplaintofrightlowerquadr ant abdominal pain, a computed tomography (CT)wasperformed onOctober 8,2002.Itre vealed ahyperdense mass at the junction of the second andthirdportionsoftheduode numanduncinateprocessof pancreas (Figure 1).The mass had infiltrative margins, w ithout localadenopathy.Furthermore, withintheliver,therewereatleast3 hyperdense lesions thatwere thoughtto pos-sibly represent hemangiomas; a fourth lesion, 5 t o 6cm in diameter, contained some areas of hypodensity,thus suggestive of a neop lastic process (Figure 2).Six days later, an esophagogastroduodenoscopy wasperf ormed,andanulceratedAmpullaofVaterwasbiopsied; thepathologyreportwassignificanto nlyforacute and chronic inflammation. One day later, mag-netic resonance imaging (MRI) of the liver was per-formed in an attempt to classify the multiple hepati clesions recognized on CT. The MRI suggested thelesions were not indicative of h emangiomata but ratherofmetastaticdeposits.Subsequently,a3.9 3.9cm mass was located associated with the head and Intravenous-Lipoic Acid/Low-Dose Naltrexone INTEGRATIVE CANCER THERAPIES 5(1); 2006pp. 83-89 83 BMB is at the Integrative Medical Center of New Mexico and NewMexico State Unive rsity, Las Cruces. DMR is in Scottsdale, Ari-zona.AJBisintheDepartmentofFamilyPr actice,UniversityofIlli-nois at Chicago, Illinois Masonic Medical Center, and th eDepartment of Family Practice, Advocate Health Center, Chicago,Illinois. Correspondence: DanielM.Rubin,4300NorthMillerRoad,Suite231, Scottsdale, AZ 85251.E-mail: rubin@r ubinmedical.com. DOI: 10.1177/1534735405285901 Figure 1 Computed tomography scan from October 8, 2002,showsa hyperdensemassat t he junction of the second and third portions of the duodenum and the uncinate pr ocess of the pancreas (circled). uncinate process of the pancreas. This prompted afine-needle aspiration of the l argest liver lesion onOctober 22, 2002, and the diagnosis of poorly differ-entia ted adenocarcinoma of pancreatic origin wasmade. Laboratory parameters reflectin g J.A.s func-tional hepatic status were at this time all within refer-ence range; in addition, a common serum tumormarkerforpancreaticcancer(CA19-9)waswithinther

eference range. Furthermore, this common markerhasremainednegativethroughoutthed iseasecourse.Following this diagnosis, chemotherapy was pre-scribed. On November 7, 2002, J.A. began a 21-day course of gemcitabine (1000 mg/m 2 ; actual dose =1800 mg; day 1 and day 8) and carboplatin (AUC 5;actualdose = 600 mg; halfdose on day1 andhalfdoseon day 8). The patient, after becoming leukopen icand thrombocytopenic and demonstrating poor sub- jective tolerance for the che motherapy, decided toseek another opinion and traveled to a well-respectedoncolo gy center. After a complete oncology workupandreviewofhispreviousrecords,J.A.,pe rhishistori-cal account, was told essentially that, given his situa-tion, any fu rther treatment would ultimately befruitless.Given this prognosis, on November 2 5, 2002, J.A.presented to the Integrative Medical Center of NewMexico(IMCNM)andw asseeninconsultationbyoneof the authors (B.M.B.). At the time of presentation,hi sreviewofsystemswaspositiveforseasonalallergies,heartburn, tinnitus, decrease in force of urinary stream, sleeping difficulty, weight loss, abdominalpain,andsev ereemotionalstressandanxiety.Medica-tions at arrival were Prevacid 30 mg, trimet hoprim/sulfamethoxazole, Mylanta, Pepto-Bismol, andRolaids. B.M.B. added alprazo lam 0.25 mg each bed-timeasneededtohelprelieveJ.A.snighttimeanxiety. An integrati ve medical program was then devel-oped and prescribed for the patient. The purpo se of this program was 3-fold: (1) nutritional support, (2)comfort and palliatio n, and (3) immune stimulation.The key therapeutic agents were intravenous a -lipoicacid (ALA) 300 to 600 mg 2 days per week and low-dose naltrexone (LDN), 4 .5 mg at bedtime. In addi-tion, a triple antioxidant regimen consisting of oral ALA (600 mg/d), selenium (200 m g 2 times per day),andsilymarin(300mg4timesaday)wasaddedtoscav-enge the products of oxidative stress that inevitably result from any serious chronic medical dis order. J.A. was also placed on a lifestyle program that includedspecific dietary advice. After the first intravenous (IV) administration of the ALA, the patient improved subjectively, prompt-ing his volunteered comment, I have increasedenerg y and a sense of well-being. The program wascontinued, and J.A. was extremely com pliant.On January 3, 2003, a repeat CT scan was per-formed using the same machin e at the same diagnos-tic radiology department. Again, the mass at the headof th e pancreas as well as the multiple hepatic lesions were demonstrated, and all le sions remained un-changed as compared to the scan of October 8, 2002(Figure 3); furthermore, no new lesions were identi-fied. The course of events was relativel y uneventful asthe patient continued on this integrative treatment plan.On Febru ary 24, 2003, a repeat CT scan was per-formed (Figure4;sameCTmachine,51daysafter theprevious CT scan and 138 days after the initial CTscan), which again demonstr ated unchanged pancre-atic primary and metastatic hepatic lesions; no newlesions were identified. As the patient continued on his treatment plan,follow-up CT sc ans were ordered at regular intervals.Both CT scans of April 21, 2003, and June 20, 2003(Figure5)revealednochangesintheexistinglesions,nor any new lesions. Anot her CT scan performed on August 19, 2003(this time on a different machine at a d ifferent Berkson et al 84 INTEGRATIVE CANCER THERAPIES 5(1); 2006 Figure 2 Computed tomography scan from October 8, 2002,shows multiple hyperdense masses within the hepatic parenchyma (circled).Figure 3 Computed tomography sca n from January 3, 2003,showsstablehepaticparenchymallesionsascompared to October 8, 2002 (arrows). institution) revealed stable primary and hepaticlesions with the potential devel opment of 2 newlesions. However, a caveat by the interpreting radiolo-gistread,Tw onewvisiblelesionsthatwerenotclearly evident on the prior scan [June 20, 2003, d ifferent institution],butagainthiscouldbeanartifactofadif-ferent phase of contra st enhancement rate/hr than adefinite new finding. Otherwise stable CT of theupp

erabdomen.ItisnotedbytheauthorsthatnoCTscan performed on J.A. has ever demonstrat ed evi-dence of biliary obstruction nor dilatation. J.A. continued on his integr ative protocol, without changes to his schedule, through March 2004, during whic h time CT images showed no changes in his dis-ease status. The patient began to feel so well, with nosymptoms of his disease, that he voluntarily discontin-ued his integrative treatment program. A positronemission tomography (PET)/CT fusion scan was per-formed on July 20, 2004, the results of which demon-strated diseas e advancement. Unfortunately, a subse-quent CT scan performed in December 2004de monstrated evidence of progressive disease at boththeprimaryandmetastaticsites(F igure6).Thelesionat the head of the pancreas had increased in size to 5cm transv ersely, and 8 hepatic lesions became recog-nizable,whilethepreviouslyidentifiedh epaticlesionsshowed a general increase in their sizes. In December2004, because of the unsatisfactory scan results, J.A.resumed the IMCNM program. Since that ti me, J.A.hascontinuedtoimprovesubjectively,andherealizedno disease progression in a June 2005 CT scan. Discussion The overall prognosis for patients with carcinoma of the pancreas is poor: the a verage length of survival af-ter diagnosis ranges from 3 to 6 months. 1 Surgical re-section is generally not an option for people withmetastatic pancrea tic cancer, and patients with ad- vanced metastatic disease rarely survive more than afewmonths.Thecurrentdogmaconcerningthisissueisthattreatmentshouldconcentra teonthealleviationofpainandtheimprovementofqualityoflifewithpar-ticipation from palliative medical personnel. 2 This leaves few options for such patients beyondchemotherapy and clinical trials . In this instance, J.A.chose to follow an integrative medical program that incl udedintravenousALA300to600mgtwiceaweek,LDN3to4.5mgatbedtime,theoraltripleantioxi dant therapy protocol (developed by B.M.B.) consisting of (1) ALA 300 mg orally 2 times a day, (2) selenium 200 m g orally 2 times a day, and (3) silymarin 300 mg 4timesaday,alongwith3profession al-strengthvitaminBcomplexcapsuleseachday.Itwasalsosuggestedthat he follow the I MCNM lifestyle program including astrict dietary regimen along with a stress-red uctionand exercise program.That J.A. has had comparatively stable disease formor ethana3-yearperiodisaremarkableclinicalfind-ing and prompts this report. It is t he opinion of the Intravenous-Lipoic Acid/Low-Dose Naltrexone INTEGRATIVE CANCER THERAPIES 5(1); 2006 85 Figure 4 Computed tomography scan from February 24, 2003,showsstablehepaticparen chymallesionsascompared to January 3, 2003 (arrows).Figure 5 Computedtomographys canfromJune20,2003,shows stable hepatic parenchymal lesions as compared to Febru ary 24, 2003 (arrows).Figure 6 Computed tomography scan from December 2004 shows increase in size of the primary pancreatic lesion and increase in the number of the hepatic parenchymal lesions as compared to the June 20, 2003 scan (18- mont h interval). authors that the lack of progression of J.A.s diseasecannot be solely attributed to the single dose of che-motherapy he received. It has been reported that gemci tabines effect on response rate and survival isdisappointing. 3 Nodataexistdeterminingresponsetopartial, moreover a single dose, of this drug ei theralone or in combination.The stability of J.A.s disease is thus attributable t othe integrative program developed by one of theauthors (B.M.B.). This is furthe r evidenced by thequickprogressionofJ.A.sprimaryandhepaticlesionsafter his volunt ary discontinuation of his integrativeand successful treatmentan unfortunate but not uncommon decision. Many patients, despite strongencouragement from their phy sicians, will discon-tinuetheirtreatments,inwholeorinpart,whenfaced withbetterhe

alth,diminishingfinancialresources,orboth. The former is a subjective sensation often real-ized by patients when undergoing a treatment planaimedatimprovingthei roverallhealthandasaresult promoting an autogenous antitumor response. Non-medic ally trained patients tend to associate improvedsense of well-being and reductio n of paraneoplasticsymptomswiththenotionthattheyareimprovingandthat continued tr eatment may not, indeed, be neces-sary. In addition, because nonconventional med icaltreatments are generally not covered by most insur-ance plans, long-term car e of this type can become afinancial burden, forcing a discontinuation of theirt reatments despite their desires or those of the treat-ingphysician.Thus,itbecome s thedutyofintegrativephysicians to bring to public attention, via publica-tion, casesinwhichsuchtreatmentplanshavedemon-strated success. When J.A. first present ed to the clinic (IMCNM),his quality of life was poor. He was losing weight,exha usted both physically and emotionally, and expe-riencing almost constantabdomina l pain andnausea.However, as mentioned above, after only 1 treatment of intraven ous ALA, his symptoms began to resolve.Improvement in quality of life is a parti cular strengthof nutritional programs, and its inclusion in a treat-ment plan fo r someone with advanced pancreaticcancer may be essential.People with metastatic pancreatic cancer often suf-fer from weight loss. The mechanism behind this isg enerally well understood and involves a complexinterplayofproinflammtorybiologic alresponsemod-ifiers 4 ; however, such pathways will not be reiteratedherewith. From a clinical point o f view, and for J.A.scase in particular, maintenance of body weight andprovision of normal protein-calorie nutritional statusisofparamountimportance.Asweightloss continues,an individuals appetite generally diminishes, thusaccelerating the loss of lean body mass, which thenleavesthepatientwithevenlessendogenousresourcesto maintain health and fight disease. It is probable,from the course of this case, that had J.A. continuedon his course of chemotherapy, he quite possibly would h ave developed frank cachexia followed by thedeleterious consequences of such a s yndrome,including death.The first key component in J.A.s treatment proto-colwasAL A.Itischieflyanantioxidant,whichhasalsobeen shown to influence a variety of biol ogical pro-cessesassociatedwithoxidativestressincludingdiabe-tes, liver disease, and cancer. 5-8 ALA is a naturally occurring cofactor that is active in an assortment of enzyma tic complexes that control metabolism. Therehavebeenanumberofarticlessuggestingt heutilityof ALA in the treatment of various cancers. One articlereported that A LA induced hyperacetylation of his-tones. 9 In this study, human cancer cell lines becameapoptotic after being exposed to AL A, while the sametreatment of normal cell lines did not induceapoptosis. Another indication of a mechanism whereby ALA might discourage the growth of cancer cel ls is its abil-ity to stabilize NFk B transcription factor. 10 Th1- andTh2-mediated immune system cells identify and react to pathogenic insult s with various cell membranereceptors.Mostofthesereceptorsinitiateacascadeof sig nal transduction events that eventually activate themaster transcription factor NFk B. NFk B is able tobindtoDNAafterthephosphorylationandubiquitin-mediated deactivation o f its inhibitor I k B and toaffect the rate of transcription of certain deleteriousgenes that have N Fk B binding sites. Because of this,NF-

k B plays a significant role in the regulation of inflammatory-induced gene functi on. High doses of ALA, when added to cell culture, have been shown toinhibit th e activation of NFk B. 11,12 Additional data have demonstrated evidence of amechanism by which ALA may contr ibute to the ther-apy for malignant disease: ALA can stimulateprooxidant-driven apoptosis in human colon cancercells. This process is activated by an increased uptakeof oxidizable substrates into the mitochondrion. 8 Inanotherstudy,ALAsynergisticallyimprovedvitaminCcytotoxicity against cancer cel ls in tissue culture. 13 Unlike ascorbate alone, ALA was equally effectiveagainst proliferating and nonpr oliferating cells.One study evaluated an extensive population of peoplewithadvan cedcancerforthebiologicalconsid-erations that are relevant to cancer cachexia. 14 Theparameters studied were serum levels of proinflam-matory cytokines (IL-1 b , IL-6, TNFa ), IL-2, acute-phase proteins (C-reactive protein and fibrinogen),leptin, and ot hers applicable to oxidative stress, suchas reactive oxygen species, endogenous antioxidant Berkson et al 86 INTEGRATIVE CANCER THERAPIES 5(1); 2006 enzymes such as glutathione peroxidase, andsuperoxide dismutase. The authors obs erved that patients with advanced cancer exhibit a chronicinflammatory state wit h high-grade oxidative stress.The article also suggests that antioxidant agents suchas ALA can stimulate the development and matura-tionofcancer-fightinglymphoc ytes.Therefore,inthis way, ALA can promote the functional restoration of the imm une system in individuals suffering theoxidative stress that results from advanc ed cancer.In another study, ALA was shown to increasehomocysteine concentrations within cancer cells incertain established cancer cell lines. 15 The increasedhomocysteine concentrations were toxic to the malig-nant cells. Ano ther study demonstrated the effects of ALA onthe proliferation of mitogen-stimul ated humanperipheral blood lymphocytes in comparison to itseffectsontheprolifera tionof2leukemicT-celllines. 16 The discriminating toxicity of ALA toward the cancercell lines was shown by elec tron microscopy and wasdue to the induction of apoptosis. In addition, ALA notic eably increased theinduction of IL-2 mRNA andIL-2proteinsecretionincancercells.T heauthorssug-gested that the differential effects of ALA on normaland leukemic T lymphocytes may specify a new path- way toward development of therapeutic agent s forcancer. Anotherrelevantarticledemonstratedtheabilityof ALA to correct the most significant functional defectsof peripheral blood mononuclear cells (PBMC) iso-lated from advanced-stage cancer patients. 17 Twenty patients (mean age = 64.6 years) with advanced can-cers of the lung, ovar y, endometrium, and head andneck were examined. The serum levels of IL-1 b , IL-2,IL-6, TNFa , and sIL-2R were significantly higher inthose with cancer thanin patients with

no known can-cers.TheadditionofALA(0.001mM)intothePBMCculturessignificantlyincre asedtheresponseofPBMCisolated from cancer patients and healthy subjects. After 2 4 and 72 hours of culture, the expression of CD25 and CD95 on PBMC isolated from cancerpatientswas significantly lower thanthatof PBMC iso-lated from healthy su bjects. The addition of ALA intothese cultures significantly increased the perce ntageof cells expressing CD25 as well as those expressingCD95.ALAthushadapositiv eeffectonseveralimpor-tant T-cell functions in people with advanced-stagecancer. LDN was the second key ingredient in this case.Nocturnally dosed LDN blocks endo genous opiatereceptors, a short-lasting effect. During this receptorblockade,the bodyproduceslargeamountsofopiatesin response to the positive feedback, which bec omeavailabletoandsaturatesaidreceptors,oncetheLDNhas been cleared from them. Opi ates are powerfulinducers of the Th1 immune response: in this sense,then, LDN pr oduces an indirect immune response.LDN has a stimulatory effect on immune cells via anindirect interaction with their opiate receptors, whereashigh-dosenaltrexo nehasaninhibitoryeffect.The widely recognized pharmacologic effect of nal-trexon e is the competitive inhibition of membrane-based opiate receptors that conseque ntly produce anopiateblockade.Asaresultofthisaction,patientswhoare addicted to o piates or are chronic ethyl alcoholusers will not feel the normal high and should beinclined to discontinue these recreational activities.For this reason, naltrex one is considered an opiateantagonist.Zagon and McLaughlin 18 reported that very low-dose naltrexone slowed the growth of neuroblastomacells i n culture and suggested that it therefore may have a role in the treatment of ce rtain cancers. In a2003article,thesameauthorssuggestedthatthemod-ulation of canc er cell growth in tissue culture was not the result of alterations in apoptosis or necrosis but from some other pathway. 19 Malignant astrocytomas are believed to be incur-able;therapyforsuchisaimedatpall iationandoverallsurvival. Lissoni et al 20 reported on the treatment of malignant astrocytomas with the administration of n altrexoneplusradiotherapy(RT).Thetumorregres-sion rate in patients treated with RT plus naltrexone was slightly higher than that of those treated with RTalone, but the percentage of those surviving at 1 year was significantly higher in pati ents treated with RTplus naltrexone than in those treated with RT alone(5/10 vs 1/11, P < .05).In a later article, Lissoni et al 21 reported escalationofIL-2-dependentanticancerimmunitybytheadmin-istration of mel atonin (MLT) plus naltrexone. Theresearchers found that these 2 agents were able tostimulate the Th1 and suppress the Th2 lymphocyteresponse.Theresultsoftheirst udyalsosuggestedthat NTX amplified the lymphocytosis obtained by IL-2plusMLT.Ina ddition,theauthorswrotethatinviewof thefactthatlymphocytosisrepresentsthemostimp or-tant favorable prognostic variable predicting theanticancer efficacy of IL-2 immunotherapy, the addi-tion of MLT and naltrexone to IL-2-containing regi-mens warrants further testing.Bihari 22 first used LDN to treat people with AIDS:given his promising results, he later u sed LDN for thetreatment of people with cancer. Over the years, headministeredLD Nto450patientswithcancer,mostof whom had failed the standard treatments. 23,24 Accord-ing to Bihari, of 354 patients who had regular follow-ups, 86 showed sig ns of noteworthy tumor shrinkage(at least a 75% reduction in tumor bulk), and at least Intravenous-Lipoic Acid/Low-Dose Naltrexone INTEGRATIVE CANCER THERAPIES 5(1); 2006 87

125 others were reported to have stabilized andappeared to be moving toward remi ssion. Conclusion In this case report, we describe the treatment of a 46- year-old man who was dia gnosed with metastatic pan-creatic cancer in October 2002. He was initially surveyedandstagedbyalocaloncologyteamandtreated withastandardchemotherapy regimen. Afterasingletreatmentofgemcitabineandcarboplatin,thepatient becameleukopenicand thrombocytopenicandcouldnot tolerate any further chemotherapy. In addition,even with the standard chemotherapy protocol, hiscancer progressed. J.A. then arrived at the office of one of the authors(B.M.B.) and was promptly started on a progr am of intravenous ALA, LDN, and a healthy lifestyle pro-gram. During the period from October 2002 to pres-ent (December 2005), J.A.s pancreatic cancer withmetast ases to the liver was followed closely by regularoffice visits and CT and PET sc ans, and he hasremained mostly stable (Figure 7). It is interesting tonote that J.A.s disease progressed rapidly when he went off the ALA-LDN therapy; however, i t stabilizedquickly when he resumed the treatment. J.A. went back to work soon a fter he started the ALA-LDNintegrativetreatmentprotocolandremainsfreeofsymptomsa t3yearsand3months.Theauthorsbelieve thatsince mostpeople withmetastaticpancre-at iccancersuccumbtotheirdiseasemiserablywithina very short time, the 39-month surv ival time with non-progressive disease reported here represents abench-mark in o ncology. People with metastatic pancreaticcancermore oftendiefromtheirdisease or complica-tions thereof within 6 months and usually after a very stressful and pa inful course. The report above is thusof great importance.In summary, the integr ative therapy described inthis article may have the possibility of extending the life of a patient who is customarily considered termi-nal. This was accomplished with a program of univer-sal antioxidants, one that bears known antitumoractivi ty (ALA) and an opiate-blockading agent that can stimulate an endogenous immune response. Theauthors believe that biomedical science will one day develop a cure for metastatic pancreatic cancer, per-haps via gene therapy or another biologic al-type plat-form. But until such protocols come to market, andmoreover evolve a ndbecome realized, theALA/LDNtherapy should be considered given its lack of toxi city at levels reported herein, ready availability, and itseffect on J.A., the t rue subject of this report.B.Berksondeclaresnofinancialinterestinthesub-stancesd iscussedinthispaperbutuseslipoicacidandnaltrexone in his medical practice. References 1. van StiegmannG,BornmanP,TerblancheJ.Carcinomaofthepancreas at Groote Schuur H ospital, 1975-1979. S Afr Med J .1981;60:97-99.2. BornmanP, BeckinghamIJ. ABC of diseasesof liver, pancreas,and biliary system: pancreatic tumours. BMJ . 2001;322:721-723.3. Choi SB, Lee Hy, Yuh YJ, Kim SR. A phase 2 study of combin a-tion chemotherapy with gemcitabine, 5-florourouracil, andcisplantinforadvanced pancreaticcancer[inKorean]. Korean J Gastroenterol . 2005;45:348-353.4. Brown TT, Zelnik DL, Dobs AS. Fish oil supplementation inth e treatment of cachexia in pancreatic cancer patients. Int J Gastrointest Cancer . 2003;34:143-150.5. ZieglerD.Thiocticacidforpatientswithsymptomaticdiabeticpoly neuropathy: a critical review. Treat Endocrinol . 2004;3:173-189.6. BerksonBM.Aconservativetripleantioxidantapproachtothetreatme nt of hepatitis C. Combination of alpha lipoic acid(thioctic acid), silymarin, a nd selenium: three case histories. Med Klin (Munich) . 1999;94(suppl 3):84-89.7. Berkson BM. Thioctic acid in treatment of hepatotoxi c mush-room ( Phalloides ) poisoning. N Engl J Med

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