FoU i Västra Götalandsregionen
En fas 2 studie av per oral behandling med digitoxin vid hormonrefraktär prostata-
cancer.
En fas 2 studie av per oral behandling med digitoxin vid hormonrefraktär prostata-
cancer.

Project number : 2151
Created by: Johan Haux, 2007-04-04
Last revised by: Pernilla Ohlin, 2009-08-10
Project created in: FoU i Västra Götalandsregionen

Not uppdated, final reminderNot uppdated, final reminder

1.Översiktlig projektbeskrivning

Engelsk titel

A pilot phase II study of digitoxin for Androgen-Independent Prostate Cancer (AIPC)

Populärvetenskaplig sammanfattning av projektet

Prostate cancer is the most common cancer among men in Sweden. Every year about 7600 men are diagnosed with prostate cancer. The incidence has increased the last years mainly due to increased diagnostic activity and an increased life span of the population (1).

Since more than 50 years androgen ablation has been a cornerstone in the treatment. Most patients with metastatic disease will initially respond to endocrine therapy, however, the effect is temporary and the median time of duration of response is about 18 months. Survival time after secondary progress, i.e. when the disease has become androgen independent, is approximately 1 year (1).

Until recently no clinical studies had shown any impact on survival that could be attributed to second line therapy. In 2004 it was reported from two studies, TAX 327 and SWOG 9916, that taxotere has significant effects in men with hormone independent prostate cancer. Prior to taxotere, no chemotherapy drug has ever shown a survival benefit for men with prostate cancer resistant to hormone therapy.

The TAX 327 study showed that the median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel (2).

In the SWOG 9916 study it was shown that in an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test)(3). Thus, we have a lot more to wish concerning effectiveness of drugs for this disease.

Most often patients with AIPC present without measurable disease. Thus, conventional criteria for objective response are frequently not applicable. On the other hand biochemical response can be assessed by repeated serum PSA (S-PSA) measurements. Actually, eligibility and response guidelines for phase II clinical trials in these patients have been developed by the Prostate-Specific Antigen (PSA) Working group (4). PSA has been shown to be useful in this setting when new treatments are evaluated in patients with AIPC.

Digitalis and cancer

During our work on anti-cancer molecules utilized by the innate immune system in humans, we found a rationale to examine the effects of digitalis on malignant cells (5,6,7). Since ancient times reports have indicated that digitalis may have anti-cancer effects and in our laboratory studies digitalis, especially in the form of digitoxin, induced apoptosis in different types of cancer cells in clinically relevant concentrations (8,9). For prostate cancer we used 4 different human cell lines, three androgen independent (DU-145, PC-3 and TSU – prl) and one androgen dependent LNCaP. These four cell lines were sensitive for digitoxin (10). The digitoxin treated prostate cancer cells that survived also accumulated in the G2M phase of the cell cycle. That might indicate that they will be more sensitive for irradiation as we have shown for breast cancer cell lines (11). The cell death induction by digitoxin is not dependent on functional p53. Subsequent studies from several different institutes, among them the MD Anderson Cancer Center in Texas, have confirmed that prostate cancer cells are sensitive for digitalis (12,13,14)

Further, we found that digitoxin seems to be the most potent of the clinically used digitalis derivatives concerning the anti-cancer effects. That has also been supported by other studies (15).

Since several decades the inhibition of the ubiquitous Na+/K+ATP:ase has been the well known working mechanism of digitalis (16). Interestingly, already in 1993 it was proposed that the Na+/K+ATP:ase might be the actual androgen receptor of the prostate (17). It is evident that not just the inhibition of the Na+/K+ATP:ase can explain all the anticancer effects (18). Recently we have learnt much more concerning mechanisms of action of digitalis. Digitoxin is a potent inhibitor of the transcription factor NF-kB and inhibits production of pro-inflammatory cytokines such as TNF-α and IL-8 (19,20).

The last years we have learnt that infection/inflammation and the associated pro-inflammatory cytokines have great impact, not only on well known inflammatory diseases such as Mb. Crohn, ulcerative colitis, but also on cancer (21,22). Inhibition of these pro-inflammatory cytokines also inhibit angiogenesis (23). Thus, drugs that inhibit NF-kB, such as thalidomide, and now digitoxin, are of interest for several, seemingly diverse diseases, but on the molecular level dependent on some of the same mechanisms (24). The latest screening procedures on gene level for potential anti-cancer drugs also point out digitoxin. (25).

The common picture is that drug candidates that exhibit anti-cancer effects in vitro fail in clinical cancer studies. Thus, to learn more about eventual impact on cancer we performed a study to examine cancer in a population taking digitoxin for cardiac conditions. However, the age is high and the morbidity and mortality due to cardiac disease are high in the population taking digitoxin. Eventual anti-cancer effects would easily “drown” in this study set-up. Despite that, an anti-cancer effect of digitoxin was detected for kidney/urinary tract cancers and leukemia/lymphoma (26).

The indications for digitoxin treatments today are cardiac congestion and supraventricular tachyarrhtmias. Studies on healthy volunteers that take digitoxin show a decrease of diastolic blood pressure and heart rate, especially during rest (27). Thus, digitoxin in doses used for the cardiac indications seems not to give any alarming side effects in humans without cardiac problems (28).

The anti-cancer effects of digitoxin are dose-dependent; the higher the dose, the more potent the anti-cancer effects. Thus, for cancer treatment as high concentrations as possible, without inducing toxic symptoms, should be used. For practical reasons one should aim at a concentration just beneath the recommended upper limit for treatment of cardiac disease (about 25 ng/l) (29).

Inclusion criteria

Age 40-80 years.

Life expectancy greater than 3 months.

Histologically proven carcinoma of the prostate (any T or N category) with evidence of S-PSA progression following primary hormonal treatment, i.e. hormone resistant. No clinical symptoms indicating progression of the prostate cancer should be present for inclusion, just S-PSA progression.

S-PSA level at trial entry should be greater than or equal to 5 ng/ml. S-PSA progression should be documented by two consecutive increases in S-PSA before enrollment. Each increase in S-PSA should be at least one unit and it should be at least 4 weeks between the samples.

The patient has WHO performance status 0-2.

Patient is receiving hormone therapy (i.e. an LHRH agonist and/or anti-androgen) and/or orchiectomy has been performed. Ongoing endocrine treatment should continue.

Patients must be physically, mentally and emotionally able to give informed consent.

Signed informed consent has been given.

Prior radiation therapy will be allowed, but radiotherapy during the study is not allowed. No concurrent
other chemotherapy is allowed in the study. Another malignancy is allowed if no other chemotherapy
drug is given.

Exclusion criteria

The patient has a relevant concurrent disease or baseline laboratory results, which put the patient at risk to take digitoxin; calcium, potassium and magnesium should be within the normal range. S-creatinine above 130 μmol/L and liver enzymes above 2 times the upper laboratory limit is not allowed.

Incomplete AV block or complete heart block. Patients with acute myocardial infarction, severe pulmonary disease, or advanced heart failure.

Patients with heart disease already on a cardiac glycoside are not eligible.

References:

1. Vårdprogram för Prostatacancer,
2004 (PDF-format),
Onkologist centrum södra sjukvårdsregionen.
http://www.ocsyd.lu.se/Vardprog/vardmeny.html

2. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators.
Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
N Engl J Med. 2004 Oct 7;351(15):1502-12.

3. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED.
Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.
N Engl J Med. 2004 Oct 7;351(15):1513-20.

4. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, Freidlin B, Halabi S, Hudes G, Hussain M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, Roth B, Sartor O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL, Wilding G, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group.
J Clin Oncol. 1999 Nov;17(11):3461-7.

5. Medvedev AE, Johnsen AC, Haux J, Steinkjer B, Egeberg K, Lynch DH, Sundan A,
Espevik T. Regulation of Fas and Fas-ligand expression in NK cells by cytokines and the involvement of Fas-ligand in NK/LAK cell-mediated cytotoxicity.
Cytokine. 1997 Jun;9(6):394-404.

6. Johnsen AC, Haux J, Steinkjer B, Nonstad U, Egeberg K, Sundan A, Ashkenazi A, Espevik T. Regulation of APO-2 ligand/trail expression in NK cells-involvement in NK cell-mediated cytotoxicity.
Cytokine. 1999 Sep;11(9):664-72.

7. Haux J, Johnsen AC, Steinkjer B, Egeberg K, Sundan A, Espevik T. The role of interleukin-2 in regulating the sensitivity of natural killer cells for Fas-mediated apoptosis.
Cancer Immunol Immunother. 1999 May-Jun;48(2-3):139-46.

8. Haux J.
Digitoxin is a potential anticancer agent for several types of cancer.
Med Hypotheses. 1999 Dec;53(6):543-8. Review.

9. Haux J, Lam M, Marthinsen ABL, Strickert T, Lundgren S.
Digitoxin, in non toxic concentrations, induces apoptotic cell death in Jurkat T cells in vitro.
Z-ONKOL. Zeitschrift für Onkologie. 1999; 31/1 (14-20).

10. Haux J, Solheim O, Isaksen T, Angelsen A.
Digitoxin, in non-toxic concentrations, inhibits proliferation and induces cell death in prostate cancer cell lines.
Z-ONKOL. Zeitschrift für Onkologie. 2000; 32/1 (11-16)

11. Haux J, Marthinsen ABL, Gulbrandsen M, Alfredsen AS, Johansen H, Strickert. Digitoxin sensitizes malignant breast cancer cells for radiation in vitro.
Z Onkol 1999;31: 61-65

12. McConkey DJ, Lin Y, Nutt LK, Ozel HZ, Newman RA.
Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells.
Cancer Res. 2000 Jul 15;60(14):3807-12.

13. Yeh JY, Huang WJ, Kan SF, Wang PS.
Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells.
J Urol. 2001 Nov;166(5):1937-42.

14. Smith JA, Madden T, Vijjeswarapu M, Newman RA.
Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin.
Biochem Pharmacol. 2001 Aug 15;62(4):469-72.

15. Johansson S, Lindholm P, Gullbo J, Larsson R, Bohlin L,
Claeson P. Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells.
Anticancer Drugs. 2001 Jun;12(5):475-83.

16. Pharmacotherapy: “A Pathophysiologic Approach”
Joseph T. Dipiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey Appleton & Lange; 3rd edition 1998

17. Farnsworth WE.
Na+,K(+)-ATPase: the actual androgen receptor of the prostate?
Med Hypotheses. 1993 Oct;41(4):358-62. Review.

18. Haux J.
Digitalis; impinges on more than just the (ion-) pump.
Med Hypotheses. 2002 Dec;59(6):781-2.

19. Srivastava M, Eidelman O, Zhang J, Paweletz C, Caohuy H, Yang Q, Jacobson KA, Heldman E, Huang W, Jozwik C, Pollard BS, Pollard HB. Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells.
Proc Natl Acad Sci U S A. 2004 May 18;101(20):7693-8.

20. Yang Q, Huang W, Jozwik C, Lin Y, Glasman M, Caohuy H, Srivastava M, Esposito D, Gillette W, Hartley J, Pollard HB. Cardiac glycosides inhibit TNF-{alpha}/NF-{kappa}B signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor.
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9631-6.

21. Balkwill F, Mantovani A.
Inflammation and cancer: back to Virchow?
Lancet. 2001 Feb 17;357(9255):539-45. Review.

22. Haux J.
Infection and cancer.
Lancet. 2001 Jul 14;358(9276):155-6.

23. Gordon JN, Goggin PM.
Thalidomide and its derivatives: emerging from the wilderness.
Postgrad Med J. 2003 Mar;79(929):127-32. Review.

24. Haux J
Old drugs – new uses
http://pmj.bmjjournals.com/cgi/eletters/79/929/127#233

25. Johnson PH, Walker RP, Jones SW, Stephens K, Meurer J, Zajchowski DA, Luke MM, Eeckman F, Tan Y, Wong L, Parry G, Morgan TK Jr, McCarrick MA, Monforte J. Multiplex gene expression analysis for high-throughput drug discovery: screening and analysis of compounds affecting genes overexpressed in cancer cells.
Mol Cancer Ther. 2002 Dec;1(14):1293-304.

26. Haux J, Klepp O, Spigset O, Tretli S. Digitoxin medication and cancer; case control and internal dose-response studies.
BMC Cancer. 2001;1(1):11.

27. Grossmann M, Jamieson MJ, Kirch W. Effects of digoxin and digitoxin on circadian blood pressure profile in healthy volunteers.
Eur J Clin Invest. 1998 Sep;28(9):701-6.

28. Grossmann M. Effects of cardiac glycosides on 24-h ambulatory blood pressure in healthy volunteers and patients with heart failure.
Eur J Clin Invest. 2001;31 Suppl 2:26-30. Review.

29. http://www.felleskatalogen.no

Typ av projekt

Forskningsprojekt

MeSH-termer för att beskriva typ av studier

checked Klinisk prövning (Clinical Trial)
checked Klinisk prövning, fas II (Clinical Trial, Phase II)
checked Pilotstudier (Pilot Projects)


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MeSH-termer för att beskriva ämnesområdet

information Added MeSH terms
Drug Therapy
Description missing
Therapeutic Human Experimentation
Human experimentation that is intended to benefit the subjects on whom it is performed.
Prostatic Neoplasms
Tumors or cancer of the PROSTATE.
Prostatic Diseases
Pathological processes involving the PROSTATE or its component tissues.
Digitoxin
A cardiac glycoside sometimes used in place of DIGOXIN. It has a longer half-life than digoxin; toxic effects, which are similar to those of digoxin, are longer lasting. (From Martindale, The Extra Pharmacopoeia, 30th ed, p665)
Digitalis
A genus of toxic herbaceous Eurasian plants of the SCROPHULARIACEAE which yield cardiotonic DIGITALIS GLYCOSIDES. The most useful species are Digitalis lanata and D. purpurea.

Projektets delaktighet i utbildning

checked Ej del i utbildning


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2. Projektorganisation och finansiering

Arbetsplatser involverade i projektet

information Added workplaces
Landsting - Västra Götalandsregionen - Specialiserad vård - Skaraborgs sjukhus

Medarbetare

Ulrik Albertsen
Läkare, Kirurg- och urologkliniken
Hans Hedelin
Läkare, Urologkliniken och FoU-centrum, Skaraborgs Sjukhus
Karin Jonsson
Sjuksköterska, Kirurgkliniken, Kärnsjukhuset

3. Processen och projektets redovisning

Hur långt har projektet framskridit?

Rekrytering/datainsamling pågår

Projektstart (när planeringen påbörjas och börjar dokumenteras skriftligt)

2007-03-01

Datum då projektet är slutrapporterat

2008-12-31

En fas 2 studie av per oral behandling med digitoxin vid hormonrefraktär prostata-
cancer., from FoU i Västra Götalandsregionen
http://www.fou.nu/is/vgr/project/2151