LDN and Cancer

Clinical trials and study data on LDN in the treatment in cancer.

Clinical Trial and Study Data

 

Liu WM, Scott KA, Dennis JL, Kaminska E, Levett AJ, Dalgleish AG. Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy. Int J Oncol. 2016;49(2):793‐802. doi:10.3892/ijo.2016.3567.  Published online on: Tuesday, June 7, 2016

  • Affiliations: Department of Oncology, Institute for Infection and Immunity, St. George's University of London, London SW17 0RE, UK

Abstract

It has been reported that lower doses of the opioid antagonist naltrexone are able to reduce tumour growth by interfering with cell signalling as well as by modifying the immune system. We have evaluated the gene expression profile of a cancer cell line after treatment with low-dose naltrexone (LDN), and assessed the effect that adapting treatment schedules with LDN may have on enhancing efficacy. LDN had a selective impact on genes involved with cell cycle regulation and immune modulation. Similarly, the pro-apoptotic genes BAD and BIK1 were increased only after LDN. Continuous treatment with LDN had little effect on growth in different cell lines; however, altering the treatment schedule to include a phase of culture in the absence of drug following an initial round of LDN treatment, resulted in enhanced cell killing. Furthermore, cells pre-treated with LDN were more sensitive to the cytotoxic effects of a number of common chemotherapy agents. For example, priming HCT116 with LDN before treatment with oxaliplatin significantly increased cell killing to 49±7.0 vs. 14±2.4% in cultures where priming was not used. Interestingly, priming with NTX before oxaliplatin resulted in just 32±1.8% cell killing. Our data support further the idea that LDN possesses anticancer activity, which can be improved by modifying the treatment schedule.

Related Articles

 


 

Schwartz L, Buhler L, Icard P, Lincet H, Steyaert JM. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res. 2014;34(2):973‐980.

Abstract

BACKGROUND:  The combination of hydroxycitrate and lipoic acid has been demonstrated by several laboratories to be effective in reducing murine cancer growth 

PATIENTS & METHOD: All patients had failed standard chemotherapy and were offered only palliative care by their referring oncologist. Karnofsky status was between 50 and 80. Life expectancy was estimated to be between 2 and 6 months. Ten consecutive patients with chemoresistant advanced metastatic cancer were offered compassionate metabolic treatment. They were treated with a combination of lipoic acid at 600 mg i.v. (Thioctacid), hydroxycitrate at 500 mg t.i.d. (Solgar) and low-dose naltrexone at 5 mg (Revia) at bedtime. Primary sites were lung carcinoma (n=2), colonic carcinoma (n=2), ovarian carcinoma (n=1), esophageal carcinoma (n=1), uterine sarcoma (n=1), cholangiocarcinoma (n=1), parotid carcinoma (n=1) and unknown primary (n=1). The patients had been heavily pre-treated. One patient had received four lines of chemotherapy, four patients three lines, four patients two lines and one patient had received radiation therapy and chemotherapy. An eleventh patient with advanced prostate cancer resistant to hormonotherapy treated with hydroxycitrate, lipoic acid and anti-androgen is also reported. 

RESULTS:  One patient was unable to receive i.v. lipoic acid and was switched to oral lipoic acid (Tiobec). Toxicity was limited to transient nausea and vomiting. Two patients died of progressive disease within two months. Two other patients had to be switched to conventional chemotherapy combined with metabolic treatment, one of when had a subsequent dramatic tumor response. Disease in the other patients was either stable or very slowly progressive. The patient with hormone-resistant prostate cancer had a dramatic fall in Prostate-Specific Antigen (90%), which is still decreasing.

CONCLUSION: These very primary results suggest the lack of toxicity and the probable efficacy of metabolic treatment in chemoresistant advanced carcinoma. It is also probable that metabolic treatment enhances the efficacy of cytotoxic chemotherapy. These results are in line with published animal data. A randomized clinical trial is warranted. 

KEYWORDS:  Hydroxycitrate; advanced cancer; alpha lipoic acid; low-dose naltrexone; metabolism


 

Meng J, Meng Y, Plotnikoff NP, Youkilis G, Griffin N, Shan F. Low dose naltrexone (LDN) enhances maturation of bone marrow dendritic cells (BMDCs). Int Immunopharmacol. 2013;17(4):1084‐1089. doi:10.1016/j.intimp.2013.10.012

Abstract

It has been demonstrated previously that immune cell activation and proliferation were sensitive to the effects of naltrexone, a non-peptidic δ-opioid receptor selective antagonist and opioid receptors on BMDCs have been detected [1]. However, there is little prior data published on naltrexone and DCs. Therefore, we hypothesized that LDN could exert modulating effect on BMDCs. In present study, we studied influence of LDN on both phenotypic and functional maturation of BMDCs. Changes of BMDC post-treatment with LDN were evaluated using conventional light microscope and transmission electron microscopy (TEM); flow cytometry(FCM); cytochemistry; acid phosphatase activity(ACP) test; FITC-dextran bio-assay; mixed lymphocytes and enzyme-linked immunosorbent assay (ELISA). We have found that LDN enhances maturation of BMDCs as evidenced by 1) up-regulating the expression of MHC II, CD40, CD83, CD80 and CD86 molecules on BMDCs; 2) down-regulating the rates of pinocytosis and phagocytosis accompanied by the results of decreased ACP, and FITC-dextran bio-assay; 3) mounting potential of BMDCs to drive T cell; and 4) inducing secretion of higher levels of IL-12 and TNF-α. It is therefore concluded that LDN can efficiently promote the maturation of BMDCs via precise modulation inside and outside BMDCs. Our study has provided meaningful mode of action on the role of LDN in immunoregulation, and rationale on future application of LDN for enhancing host immunity in cancer therapy and potent use in the design of DC-based vaccines for a number of diseases.


 

Parikh N, Goskonda V, Chavan A, Dillaha L. Pharmacokinetics and dose proportionality of fentanyl sublingual spray: a single-dose 5-way crossover study. Clin Drug Investig. 2013;33(6):391‐400. doi:10.1007/s40261-013-0079-8

    Abstract

    BACKGROUND:  Fentanyl sublingual spray is a novel formulation of fentanyl for sublingual delivery that was designed to enhance the rate and extent of absorption of fentanyl for management of breakthrough cancer pain (BTCP). 

    OBJECTIVES:  The primary objective of this study was to determine the pharmacokinetics and dose proportionality of 5 different doses (100, 200, 400, 600, and 800 μg) of fentanyl sublingual spray in healthy subjects under fasted conditions (part A); the secondary objective was to assess the effects of temperature and pH in the oral cavity on relative bioavailability of fentanyl (part B). 

    METHODS:  Analyses were performed on venous blood samples drawn 5 min to 36 h after administration of fentanyl sublingual spray (Subsys(®), Insys Therapeutics, Inc., Chandler, AZ, USA). Part A of this phase I study was a 5-treatment, 5-sequence, 5-period crossover study in which subjects received a single treatment of each of the 5 fentanyl sublingual spray doses. Dose proportionality was assessed using analysis of variance and linear regression techniques. Part B was a 5-treatment, 2-sequence, 5-period crossover study in which subjects received a single assigned dose of fentanyl sublingual spray 200 μg under the following 5 conditions: no pretreatment, pretreatment with cold or hot beverage, and pretreatment with low- or high-pH beverage. Naltrexone was administered to block potential opioid effects associated with fentanyl. Adverse events (AEs) were monitored and recorded throughout the study. 

    RESULTS:  Fifty-three subjects (15 men, 38 women; mean age, 31 years) were enrolled in part A. Fourteen subjects (11 men, 3 women; mean age, 32 years) were enrolled in part B. The first quantifiable mean plasma concentrations of fentanyl were observed at the first sample time (5 min) for all doses. Mean maximum plasma concentration (C(max)) increased with increases in dose, whereas median time to reach C max (t max) tended to decrease with increases in dose. The dose-normalized C(max), area under the plasma concentration-time curve from time zero to infinity (AUC∞), and AUC from time zero to time of last measurable concentration (AUClast) values were linear and consistent with dose proportionality across the 100-800 μg dose range. Pretreatment of the oral cavity with a cold or hot beverage, or low- or high-pH beverage, did not appreciably alter fentanyl absorption (C(max) and AUC∞ values). The most commonly reported AEs were nausea and vomiting. 

    CONCLUSION:  In healthy subjects, administration of fentanyl sublingual spray produced a rapid rise in fentanyl plasma concentrations. Dose-dependent parameters (C max and AUC) showed dose proportionality across the range of 100-800 μg. Altering the local environment of the oral cavity (temperature and pH) showed no effects on the bioavailability of fentanyl. The rapid and predictable rise in plasma fentanyl concentrations following administration of fentanyl sublingual spray corresponds with the rapid onset and duration of many BTCP episodes.


     

    Zagon IS, Donahue R, McLaughlin PJ. Targeting the opioid growth factor: opioid growth factor receptor axis for treatment of human ovarian cancer. Exp Biol Med (Maywood). 2013;238(5):579‐587. doi:10.1177/1535370213488483

    Abstract  

    The opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis is a biological pathway that is present in human ovarian cancer cells and tissues. OGF, chemically termed [Met(5)]-enkephalin, is an endogenous opioid peptide that interfaces with OGFr to delay cells moving through the cell cycle by upregulation of cyclin-dependent inhibitory kinase pathways. OGF inhibitory activity is dose dependent, receptor mediated, reversible, protein and RNA dependent, but not related to apoptosis or necrosis. The OGF-OGFr axis can be targeted for treatment of human ovarian cancer by (i) administration of exogenous OGF, (ii) genetic manipulation to over-express OGFr and (iii) use of low dosages of naltrexone, an opioid antagonist, which stimulates production of OGF and OGFr for subsequent interaction following blockade of the receptor. The OGF-OGFr axis may be a feasible target for treatment of cancer of the ovary (i) in a prophylactic fashion, (ii) following cytoreduction or (iii) in conjunction with standard chemotherapy for additive effectiveness. In summary, preclinical data support the transition of these novel therapies for treatment of human ovarian cancer from the bench to bedside to provide additional targets for treatment of this devastating disease.


     

    Davis M, Goforth HW, Gamier P. Oxycodone combined with opioid receptor antagonists: efficacy and safety. Expert Opin Drug Saf. 2013;12(3):389‐402. doi:10.1517/14740338.2013.783564

    Abstract

    INTRODUCTION:  A mu receptor antagonist combined with oxycodone (OXY) may improve pain control, reduce physical tolerance and withdrawal, minimizing opioid-related bowel dysfunction and act as an abuse deterrent. 

    AREAS COVERED:  The authors cover the use of OXY plus ultra-low-dose naltrexone for analgesia and the use of sustained-release OXY plus sustained-release naloxone to reduce the opioid bowel syndrome. The authors briefly describe the use of sustained-release OXY and naltrexone pellets as a drug abuse deterrent formulation. Combinations of ultra-low-dose naltrexone plus OXY have been in separate trials involved in patients with chronic pain from osteoarthritis and idiopathic low back pain. High attrition and marginal differences between ultra-low-dose naltrexone plus OXY and OXY led to discontinuation of development. Prolonged-release (PR) naloxone combined with PR OXY demonstrates a consistent reduction in opioid-related bowel dysfunction in multiple randomized controlled trials. However, gastrointestinal side effects, including diarrhea, were increased in several trials with the combination compared with PR OXY alone. Analgesia appeared to be maintained although non-inferiority to PR OXY is not formally established. There were flaws to trial design and safety monitoring. Naltrexone has been combined with OXY in individual pellets encased in a capsule. This combination has been reported in a Phase II trial and is presently undergoing Phase III studies. 

    EXPERT OPINION: Due to the lack of efficacy the combination of altered low-dose naltrexone with oxycodone should cease in development. The combination of sustained release oxycodone plus naloxone reduces constipation with a consistent benefit. Safety has been suboptimally evaluated which is a concern. Although the drug is commercially available in several countries, ongoing safety monitoring particularly high doses would be important.


     

    Rogosnitzky M, Finegold MJ, McLaughlin PJ, Zagon IS. Opioid growth factor (OGF) for hepatoblastoma: a novel non-toxic treatment. Invest New Drugs. 2013;31(4):1066‐1070. doi:10.1007/s10637-012-9918-3

    Abstract

    Hepatoblastoma is the most common liver malignancy in children, typically diagnosed before age 2. The survival rate for hepatoblastoma has increased dramatically in the last 30 years, but the typical chemotherapeutic agents used for treatment are associated with significant toxicity. In this report, the authors present two cases of hepatoblastoma treated with surgical resection and a novel biotherapeutic regimen that included opioid growth factor (OGF). Case #1 is an infant diagnosed with a large mass on prenatal ultrasound. After subsequent diagnosis of hepatoblastoma, she was treated with one course of neoadjuvant chemotherapy at approximately 1 week of age. Following significant complications from the chemotherapy (neutropenic fever, pneumonia and sepsis), the patient's parents declined further chemotherapy, and the infant was treated with surgical resection and opioid growth factor (OGF)/low dose naltrexone (LDN). She is currently at close to 10 years disease-free survival. Case #2 is a child diagnosed with a liver mass on ultrasound at 20 months of age, later biopsy-proven to represent hepatoblastoma. Due to existing co-morbidities including autosomal recessive polycystic kidney disease and hypertension, and indications from the biopsy that the tumor might be insensitive to chemotherapy, the parents elected not to proceed with neoadjuvant chemotherapy. The patient was treated with surgical resection and OGF/LDN, and is currently at more than 5 years disease-free survival. This case series highlights the need for less toxic treatment options than conventional chemotherapy. Modulation of the OGF-OGF receptor axis represents a promising safe and therapeutic avenue for effective treatment of hepatoblastoma.


     

    Society for Experimental Biology and Medicine. "Low dose naltrexone: Harnessing the body's own chemistry to
    treat human ovarian cancer
    ." ScienceDaily. ScienceDaily, 13 July 2011.

    Abstract

    Researchers have discovered that a low dose of the opioid antagonist naltrexone (LDN) markedly suppresses progression of human ovarian cancer transplanted into mice. LDN's antitumor action was comparable to that of chemotherapy (cisplatin, taxol). LDN combined with cisplatin but not taxol had an additive inhibitory action on tumorigenesis. LDN offers a non-toxic and efficacious biologic pathway-related treatment that may benefit patients with this deadly cancer.


     

    Donahue RN, McLaughlin PJ, Zagon IS. Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin. Experimental Biology and Medicine (Maywood, N.J.). 2011 Jul;236(7):883-895. DOI: 10.1258/ebm.2011.011096.

    Abstract

    Ovarian cancer is the leading cause of death from gynecological malignancies. Although initial therapeutic modalities are successful, 65% of these women relapse with only palliative treatments available thereafter. Endogenous opioids repress the proliferation of human ovarian cancer cells in vitro, and do so in a receptor-mediated manner. The present study examined whether modulation of opioid systems by the opioid antagonist naltrexone (NTX), alone or in combination with standard of care therapies (taxol/paclitaxel, cisplatin), alters human ovarian cancer cell proliferation in tissue culture and tumor progression in mice. Administration of NTX for six hours every two days, but not continuously, reduced DNA synthesis and cell replication from vehicle-treated controls in tissue culture. Moreover, brief exposure to NTX in combination with taxol or cisplatin had an enhanced anticancer action. Mice with established ovarian tumors and treated with a low dosage of NTX (LDN), which invokes a short period of opioid receptor blockade, repressed tumor progression in a non-toxic fashion by reducing DNA synthesis and angiogenesis but not altering cell survival. The combination of LDN with cisplatin, but not taxol, resulted in an additive inhibitory effect on tumorigenesis with enhanced depression of DNA synthesis and angiogenesis. LDN combined with cisplatin alleviated the toxicity (e.g. weight loss) associated with cisplatin. LDN treatment upregulated the expression of the opioid growth factor (OGF, chemical term ([Met(5)]-enkephalin) and its receptor, OGFr. Previous tissue culture studies have reported that OGF is the only opioid peptide with antiproliferative activity on ovarian cancer cells, with OGF action mediated by OGFr. Thus, the common denominator of intermittent opioid receptor blockade by short-term NTX or LDN on ovarian cancer proliferation and tumorigenesis recorded herein appears to be related to the OGF-OGFr axis. These preclinical data may offer a non-toxic and efficacious pathway-related treatment that can benefit patients with ovarian cancer.


     

    McLaughlin PJ, Stucki JK, Zagon IS. Modulation of the opioid growth factor ([Met(5)]-enkephalin)-opioid growth factor receptor axis: novel therapies for squamous cell carcinoma of the head and neck. Head Neck. 2012;34(4):513‐519. doi:10.1002/hed.21759

    Abstract

    Background: The opioid growth factor (OGF)-OGF receptor (OGFr) axis is a constitutively expressed biologic pathway regulating cell proliferation of squamous cell carcinoma of the head and neck (SCCHN). This study investigated modulation of the OGF-OGFr system by (1) exogenous OGF, (2) upregulation of OGFr using imiquimod, or (3) intermittent opioid receptor blockade with a low dose of naltrexone on progression of established SCCHN.

    Methods: Nude mice with visible human SCCHN SCC-1 tumors received (1) OGF or low-dose naltrexone either 1, 3, or 7 times/week or (2) imiquimod 1 or 3 times/week. Tumor growth and DNA synthesis were monitored.

    Results: OGF and low-dose naltrexone increased the latency from visible to measurable tumors up to 1.6-fold. OGF, low-dose naltrexone, and imiquimod treatment markedly reduced tumor volume and weight, and decreased DNA synthesis in tumors.

    Conclusions: Modulation of the native OGF-OGFr regulatory network in SCCHN represents a novel nontoxic and highly efficacious approach for treatment of SCCHN.

    Background: The opioid growth factor (OGF)-OGF receptor (OGFr) axis is a constitutively expressed biologic pathway regulating cell proliferation of squamous cell carcinoma of the head and neck (SCCHN). This study investigated modulation of the OGF-OGFr system by (1) exogenous OGF, (2) upregulation of OGFr using imiquimod, or (3) intermittent opioid receptor blockade with a low dose of naltrexone on progression of established SCCHN.

    Methods: Nude mice with visible human SCCHN SCC-1 tumors received (1) OGF or low-dose naltrexone either 1, 3, or 7 times/week or (2) imiquimod 1 or 3 times/week. Tumor growth and DNA synthesis were monitored.

    Results: OGF and low-dose naltrexone increased the latency from visible to measurable tumors up to 1.6-fold. OGF, low-dose naltrexone, and imiquimod treatment markedly reduced tumor volume and weight, and decreased DNA synthesis in tumors.

    Conclusions: Modulation of the native OGF-OGFr regulatory network in SCCHN represents a novel nontoxic and highly efficacious approach for treatment of SCCHN.


     

    Berkson BM, Rubin DM, Berkson AJ. Reversal of signs and symptoms of a B-cell lymphoma in a patient using only low-dose naltrexone. Integr Cancer Ther. 2007;6(3):293‐296. doi:10.1177/1534735407306358

    Abstract

    The authors believe that by the mechanisms presented, LDN demonstrates significant potential to increase disease-free as well as overall survival in people with FL. It is hoped that biomedical science will soondevelop cures for the currently incurable cancers, perhaps via gene therapy, cancer vaccines, or otherbiological platforms. Until that time, we need to considertreatments that have the potential to alter the course of cancers for the better. Especially needed are treatmentssuch as LDN that are inexpensive, demonstrate ease of compliance, and are bereft of the side effects plaguingmost currently used conventional therapies.

    Abstract

    The authors describe the long-term survival of a patient with pancreatic cancer without any toxic adverse effects. The treatment regimen includes the intravenous alpha-lipoic acid and low-dose naltrexone (ALA-N) protocol and a healthy lifestyle program. The patient was told by a reputable university oncology center in October 2002 that there was little hope for his survival. Today, January 2006, however, he is back at work, free from symptoms, and without appreciable progression of his malignancy. The integrative protocol described in this article may have the possibility of extending the life of a patient who would be customarily considered to be terminal. The authors believe that life scientists will one day develop a cure for metastatic pancreatic cancer, perhaps via gene therapy or another biological platform. But until such protocols come to market, the ALA-N protocol should be studied and considered, given its lack of toxicity at levels reported. Several other patients are on this treatment protocol and appear to be doing well at this time.


     

    Zylicz Z, Stork N, Krajnik M. Severe pruritus of cholestasis in disseminated cancer: developing a rational treatment strategy. A case report. J Pain Symptom Manage. 2005;29(1):100‐103. doi:10.1016/j.jpainsymman.2004.04.009

    Abstract

    Severe pruritus is a frequent complication of cholestasis. Both serotonin and opioids play an important role in the development of this symptom. Guidelines to provide rational management of pruritus of cholestasis do not exist. We describe a patient with complex and malignant course of pruritus. She responded to several measures proposed (among other naltrexone), but rapily became tolerant to them. Buprenorphine with an ultra low dose of naloxone was able to control her symptoms without development of tolerance until her death.
    Key words: Pruritus, itch, cholestasis, naltrexone, buprenorphine


     

    Lissoni P, Malugani F, Malysheva O, et al. Neuroimmunotherapy of untreatable metastatic solid tumors with subcutaneous low-dose interleukin-2, melatonin and naltrexone: modulation of interleukin-2-induced antitumor immunity by blocking the opioid system. Neuro Endocrinol Lett. 2002;23(4):341‐344.

    Abstract

    OBJECTIVES: The preliminary applications of the psychoneuroimmunological knowledges to the treatment of human diseases have confirmed thepossibility to amplify IL-2-dependent anticancer immunity by the pineal hormone melatonin (MLT) or by opioid antagonist, such as naltrexone (NTX), which act by activating TH1 lymphocytes or suppressing TH2 lymphocytes, respectively. At present, however, there are no data about the immunobiological effects of a concomitant administration of both MLT and NTX on IL-2-induced anticancer immunity. This preliminary study was carried out to evaluate whether the association of NTX may further enhance the lymphocytosis induced by the neuroimmunotherapy with IL-2 plus MLT. 

    MATERIALS & METHODS: The study included 14 consecutive untreatable metastatic solid tumor patients. According to a cross-over randomized study, the patients were treated during two consecutive immunotherapeutic cycles at 21-day intervals with IL-2 plus MLT alone or with IL-2 plus MLT plus NTX. IL-2 was injected subcutaneously at 3 MIU/day for 6 days/week for 4 weeks, MLT was given orally at 20 mg /day in the evening every day, and NTX was given orally at 100 mg in the morning every next day. For the immune evaluation, venous blood samples were drawn before the onset of treatment and at weekly intervals. 

    RESULTS:  Lymphocyte mean number significantly increased after both IL-2 plus MLT and IL-2 plus MLT plus NTX. However, the concomitant administration of NTX induced a significantly higher increase in lymphocyte mean number with respect to that achieved with IL-2 plus MLT alone. In contrast, the increase in eosinophil mean number was significantly higher on IL-2 plus MLT alone. 

    CONCLUSIONS:  This preliminary study shows that the association of NTX further amplifies the lymphocytosis obtained by IL-2 plus MLT. Since the lymphocytosis represents the most important favourable prognostic variable predicting the anticancer efficacy of IL-2 immunotherapy, it is probable that a cancer neuroimmunotherapy with IL-2 plus both MLT and NTX to activate TH1 and suppress TH2 cells respectively, may deserve more promising results in the treatment of human neoplasms according to the psychoneuroimnunological knowledge.