WO1992000743A1 - Use of taurolidine and/or taurultam for the treatment of tumours - Google Patents

Use of taurolidine and/or taurultam for the treatment of tumours Download PDF

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Publication number
WO1992000743A1
WO1992000743A1 PCT/EP1991/001269 EP9101269W WO9200743A1 WO 1992000743 A1 WO1992000743 A1 WO 1992000743A1 EP 9101269 W EP9101269 W EP 9101269W WO 9200743 A1 WO9200743 A1 WO 9200743A1
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Prior art keywords
taurolidine
taurultam
tumours
treatment
administered
Prior art date
Application number
PCT/EP1991/001269
Other languages
French (fr)
Inventor
John Monson
Original Assignee
Ed Geistlich Söhne Ag Für Chemische Industrie
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Filing date
Publication date
Application filed by Ed Geistlich Söhne Ag Für Chemische Industrie filed Critical Ed Geistlich Söhne Ag Für Chemische Industrie
Publication of WO1992000743A1 publication Critical patent/WO1992000743A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to the treatment of tumours by chemotherapy.
  • the antibacterial and anti-toxin drug taurolidine and the related product taurultam have recently been shown to exert a modifying effect on the toxicity of tumour necrosis factor (TNF) which is used, inter alia, in the treatment of tumours.
  • TNF tumour necrosis factor
  • Our United Kingdom Patent Application No 9005856.1 relates to combined therapy using TNF and taurolidine or taurultam.
  • taurolidine acted directly on tumours in addition to its effect on TNF.
  • taurolidine was shown to be selective in that the growth of normal cell-lines was not significantly inhibited.
  • Taurolidine and taurultam have the formulae given below:
  • Taurolidine acts by transferring three methylol groups at the site of action, taurultam being an intermediate metabolite which itself transfers a single methylol group with liberation of the very well tolerated compound taurinamide. Thus, the two compounds act by essentially the same mechanism. It should be noted that methylol transfer is to be contrasted with methyl transfer which is characteristic of many highly toxic anti-tumour drugs. Taurolidine and taurultam have low toxicity and are not cytotoxic against normal cells.
  • the taurolidine or taurultam may be administered systemically, ie. by injection or infusion, or by direct application, eg topically, to external tumours.
  • Suitable formulations for injection or infusion may comprise an isotonic solution containing one or more solubilising agents, eg polyols such as glucose, in order to provide solutions of increased taurolidine or taurultam concentration.
  • solubilising agents eg polyols such as glucose
  • concentration of taurolidine or taurultam in such solutions may be in the range 1 to 10 g/litre.
  • Taurolidine and/or taurultam may be administered in the dose range 150 to 450 mg/kg per day, preferably 300 to 450 mg/kg per day. Relatively large volumes of aqueous solutions containing taurolidine or taurultam will thus often require to be administered, containing for example lOg to 30g of taurolidine and/or taurultam. It may be convenient to administer these compounds by infusion in view of the relatively large volumes concerned, conveniently at intervals throughout the day. - 3 -
  • agents known to be involved in tumour metabolism may also advantageously be co-administered in conjunction with the above combined therapy.
  • agents include gamma-interferon, interleukin-1 and interleukin-2.
  • Cytotoxic agents such as adriamycin and actinomycin D may also be co-administered.
  • tumours to be treated may be of any type, including lymphomas, sarcomas, melanomas and carcinomas. It is particularly beneficial to use taurolidine and/or taurultam prevent the spread of metastases, especially following surgical removal of tumours.
  • the mammalian subjects are typically humans.
  • the invention also includes the use of taurolidine and/or taurultam for the treatment or prophylaxis of tumours in mammalian subjects.
  • the invention further includes the use of taurolidine and/or taurultam for the preparation of pharmaceutical compositions for the treatment or prophylaxis of tumours in mammalian subjects.
  • mice injected iv with 1.5xl0 6 B16 melanoma cells were treated with a) ip normal saline tid on days 0-10, b) ip taurolidine 4.0mg tid on days 0-10, and c) ip taurolidine 4.0mg tid on days 3-10.
  • Mice were sacrificed on day 10 and pulmonary metastases counted.
  • taurolidine treatments started on the day of tumour injection the number of pulmonary metastases was - A - significantly reduced compared either to the control group or to Group C (p ⁇ 0.05).
  • mice injected sc with 1.5 x 10 6 Meth A sarcoma cells received either no treatment or taurolidine 2mg ip bid for seven days. At seven days 90% (27/30) of the control animals had palpable tumour growth, while only 40% (12/30) of the taurolidine treated mice had detectable tumour growth (p-0.0.02).
  • Balb C mice received IP injections of meth A followed by either a)saline 0.1 ml IP BD or b) taurolidine 0.1 ml IP BD for 7 days. At 7 days 28/32 saline treated mice had ascites in comparison to 0/32 of taurolidine treated mice (p ⁇ 0.0001) . Actuarial survival of saline treated mice was also significantly impaired (p,0.005).
  • Taurolidine was tested against multiple cell lines (two tumours, one normal) using a range of doses.
  • tumour lines Preferential activity against tumour lines was demonstrated at low doses with complete cellular inhibition of tumour, but not normal cells, occurring at doses > 200 ⁇ g ml

Abstract

The present invention relates to a method of treatment or prophylaxis of tumours in mammalian subjects wherein an effective dose of taurolidine and/or taurultam is administered to a mammalian subject suffering from or at risk to tumour growth.

Description

- 1 -
USE OF TAUROLIDINE AND/OR TAURULTAM FOR THE TREATMENT OF TUMOURS
This invention relates to the treatment of tumours by chemotherapy.
The antibacterial and anti-toxin drug taurolidine and the related product taurultam have recently been shown to exert a modifying effect on the toxicity of tumour necrosis factor (TNF) which is used, inter alia, in the treatment of tumours. Our United Kingdom Patent Application No 9005856.1 relates to combined therapy using TNF and taurolidine or taurultam. In the course of these studies, it was surprisingly found that taurolidine acted directly on tumours in addition to its effect on TNF. Furthermore, such action was shown to be selective in that the growth of normal cell-lines was not significantly inhibited.
According to the present invention we provide a method of treatment or prophylaxis of tumours in mammalian subjects wherein an effective dose of taurolidine and/or taurultam is administered to a mammalian subject suffering from or at risk to tumour growth.
Taurolidine and taurultam have the formulae given below:
Figure imgf000003_0001
TAUROL I D I NE TAURUL TAM - 2 -
These compounds are ethylol transfer agents. Taurolidine acts by transferring three methylol groups at the site of action, taurultam being an intermediate metabolite which itself transfers a single methylol group with liberation of the very well tolerated compound taurinamide. Thus, the two compounds act by essentially the same mechanism. It should be noted that methylol transfer is to be contrasted with methyl transfer which is characteristic of many highly toxic anti-tumour drugs. Taurolidine and taurultam have low toxicity and are not cytotoxic against normal cells.
The taurolidine or taurultam may be administered systemically, ie. by injection or infusion, or by direct application, eg topically, to external tumours.
Suitable formulations for injection or infusion may comprise an isotonic solution containing one or more solubilising agents, eg polyols such as glucose, in order to provide solutions of increased taurolidine or taurultam concentration. Such solutions are described in our European Patent Application 253662. The concentration of taurolidine or taurultam in such solutions may be in the range 1 to 10 g/litre.
Taurolidine and/or taurultam may be administered in the dose range 150 to 450 mg/kg per day, preferably 300 to 450 mg/kg per day. Relatively large volumes of aqueous solutions containing taurolidine or taurultam will thus often require to be administered, containing for example lOg to 30g of taurolidine and/or taurultam. It may be convenient to administer these compounds by infusion in view of the relatively large volumes concerned, conveniently at intervals throughout the day. - 3 -
It is believed that other agents known to be involved in tumour metabolism may also advantageously be co-administered in conjunction with the above combined therapy. Such agents include gamma-interferon, interleukin-1 and interleukin-2.
Cytotoxic agents such as adriamycin and actinomycin D may also be co-administered.
The tumours to be treated may be of any type, including lymphomas, sarcomas, melanomas and carcinomas. It is particularly beneficial to use taurolidine and/or taurultam prevent the spread of metastases, especially following surgical removal of tumours. The mammalian subjects are typically humans.
The invention also includes the use of taurolidine and/or taurultam for the treatment or prophylaxis of tumours in mammalian subjects.
The invention further includes the use of taurolidine and/or taurultam for the preparation of pharmaceutical compositions for the treatment or prophylaxis of tumours in mammalian subjects.
The following examples are given by way of illustration only:-
Example 1
C573L/6 mice injected iv with 1.5xl06 B16 melanoma cells were treated with a) ip normal saline tid on days 0-10, b) ip taurolidine 4.0mg tid on days 0-10, and c) ip taurolidine 4.0mg tid on days 3-10. Mice were sacrificed on day 10 and pulmonary metastases counted. When taurolidine treatments started on the day of tumour injection, the number of pulmonary metastases was - A - significantly reduced compared either to the control group or to Group C (p<0.05).
Treatment Group n Mean Pulmonary Metastases ± S.E.M
Saline 25 117.3 ± 18.5
Taurolidine (D 0-10) 16 76.4 ± 14.9 Taurolidine (D 3-10) 16 103.5 ± 14.8
In a second in vivo experiment, Balb/c mice injected sc with 1.5 x 106 Meth A sarcoma cells received either no treatment or taurolidine 2mg ip bid for seven days. At seven days 90% (27/30) of the control animals had palpable tumour growth, while only 40% (12/30) of the taurolidine treated mice had detectable tumour growth (p-0.0.02). In a third series Balb C mice received IP injections of meth A followed by either a)saline 0.1 ml IP BD or b) taurolidine 0.1 ml IP BD for 7 days. At 7 days 28/32 saline treated mice had ascites in comparison to 0/32 of taurolidine treated mice (p<0.0001) . Actuarial survival of saline treated mice was also significantly impaired (p,0.005).
Example 2
Taurolidine was tested against multiple cell lines (two tumours, one normal) using a range of doses.
5 -
Cell line Concentration Inhibition of tested (μg ml) cellular metabolism
(%)
Foreskin
Fibroblasts 20 31.7
LS174T (colon) 20 84.3
Jurkat (leukaemic) 20 84.6
Preferential activity against tumour lines was demonstrated at low doses with complete cellular inhibition of tumour, but not normal cells, occurring at doses > 200 μg ml

Claims

1. A method of treatment or prophylaxis of tumours in mammalian subjects wherein an effective dose of taurolidine and/or taurultam is administered to a mammalian subject suffering from or at risk to tumour growth.
2. A method as claimed in Claim 1 wherein said taurolidine and/or taurultam is administered by injection or infusion or by direct application to external tumours.
3. A method as claimed in Claim 1 or Claim 2 wherein said taurolidine and/or taurultam is administered at a dosage in the range of 150-450 mg/kg per day.
4. A method as claimed in Claim 3 wherein said taurolidine and/or taurultam is administered at a dosage in the range of 300 to 450 mg/kg per day.
5. A method as claimed in any one of Claims 1 to 4 for the treatment or prophylaxis of lymphomas, sarcomas, melanomas and carcinomas.
6. A method as claimed in any one of Claims 1 to 5 further comprising administering to said mammalian subject separately or simultaneously cytotoxic agents or agents known to be involved in tumour metabolism.
7. A method as claimed in Claim 6 comprising further administering gam a-interferon, interleukin-1, interleukin-2, adriamycin or actinomycin D. - 7 -
8. Use of taurolidine and/or taurultam for the treatment or prophylaxis of tumours in mammalian subjects.
9. Use of taurolidine and/or taurultam for the preparation of pharmaceutical compositions for the treatment or prophylaxis of tumours in mammalian subjects.
10. A pharmaceutical composition comprising taurolidine and/or taurultum and at least one agent selected from cytotoxic agents or agents involved in tumour metabolism for separate or simultaneous administration to a mammalian subject suffering from or at risk to tumour growth.
PCT/EP1991/001269 1990-07-09 1991-07-08 Use of taurolidine and/or taurultam for the treatment of tumours WO1992000743A1 (en)

Applications Claiming Priority (2)

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GB909015108A GB9015108D0 (en) 1990-07-09 1990-07-09 Chemical compositions
GB9015108.5 1990-07-09

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19606897A1 (en) * 1996-02-13 1997-08-14 Joachim Michael Prof D Mueller Agent inhibiting tumour cell spread and metastasis in surgery of tumours
WO1999006114A2 (en) * 1997-07-31 1999-02-11 Ed Geistlich Söhne Ag Für Chemische Industrie Use of taurolidine or taurultam for the manufacture of a medicament for the prevention of metastases
EP1066830A2 (en) * 1999-06-04 2001-01-10 Ed. Geistlich Söhne Ag Für Chemische Industrie Uses and compositions for treating primary and secondary tumors of the central nervous system (cns)
WO2001039763A2 (en) * 1999-12-06 2001-06-07 Rhode Island Hospital, A Lifespan Partner Use of methylol-containing compounds for the manufacture of a medicament for the treatment of tumors
EP1201247A2 (en) 2000-10-27 2002-05-02 Ed Geistlich Söhne AG Für Chemische Industrie Treatment of tumor metastases and cancer
EP1208840A2 (en) * 2000-11-28 2002-05-29 Ed Geistlich Söhne AG Für Chemische Industrie Combination of fluorouracil and a methylol transfer agent for the treatment of tumor metastases and cancer
EP1247524A1 (en) 2001-04-03 2002-10-09 Ed. Geistlich Söhne Ag Für Chemische Industrie Composition comprising taurolidine and/or taurultam for the treatment of cancer
US6641571B2 (en) 2000-01-05 2003-11-04 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Reduction of postoperative complications of cardiopulmonary bypass (CPB) surgery
EP1377281A1 (en) * 2001-03-15 2004-01-07 Rhode Island Hospital Taurine compounds
US6753328B2 (en) 2001-10-01 2004-06-22 Rhode Island Hospital Methods of inhibiting metastases
US7151099B2 (en) 1998-07-31 2006-12-19 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Use of taurolidine and/or taurultam for treatment of abdominal cancer and/or for the prevention of metastases
WO2008029264A2 (en) * 2006-09-07 2008-03-13 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method of treating bone cancer
US7345039B2 (en) 1999-06-04 2008-03-18 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Enhancement of effectiveness of 5-fluorouracil in treatment of tumor metastases and cancer
US7479505B2 (en) 1999-12-06 2009-01-20 Geistlich Phama Ag Use of taurolidine to treat tumors
EP1797884A3 (en) * 1999-12-06 2010-02-10 Geistlich Pharma AG Use of taurolidine or taurultam for the manufacture of a medicament for the treatment of tumors of the central nervous system
US7892530B2 (en) 1999-06-04 2011-02-22 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Treatment of tumor metastases and cancer
US8030301B2 (en) 1999-06-04 2011-10-04 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Treatment of cancers with methylol-containing compounds and at least one electrolyte
US8236794B2 (en) 2003-09-29 2012-08-07 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Treatment of mesothelioma
US8304390B2 (en) 1997-07-31 2012-11-06 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method of treatment for preventing or reducing tumor growth in the liver of patient
US8394397B2 (en) 2003-03-28 2013-03-12 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Adhesive antineoplastic compositions

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Annals of the Royal College of Surgeons of England, vol. 72, 1990, M.E. Lucarotti et al.:"Antiseptic Toxicity to Breast Carcinoma in Tissue Culture: An Adjuvant to Conservation Therapy?", pages 388-392, see the whole document *
J.E.F. Reynolds: "Martindale", The Extra Pharmacopoeia, 29th Edition, 1989, The Pharmaceutical Press, (London, GB), page 162, "Taurolidine", see the whole article *

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US8304390B2 (en) 1997-07-31 2012-11-06 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method of treatment for preventing or reducing tumor growth in the liver of patient
US7151099B2 (en) 1998-07-31 2006-12-19 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Use of taurolidine and/or taurultam for treatment of abdominal cancer and/or for the prevention of metastases
US7910580B2 (en) 1999-06-04 2011-03-22 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Enhancement of effectiveness of 5-Fluorouracil in treatment of tumor metastases and cancer
US8030301B2 (en) 1999-06-04 2011-10-04 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Treatment of cancers with methylol-containing compounds and at least one electrolyte
US6815441B2 (en) 1999-06-04 2004-11-09 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Reaction products of taurultam and glucose
US7892530B2 (en) 1999-06-04 2011-02-22 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Treatment of tumor metastases and cancer
US7638511B2 (en) 1999-06-04 2009-12-29 Ed. Geistlich Sohne Ag Fur Chemische Industrie Methods and compositions for treating primary and secondary tumors of the central nervous system (CNS)
US8202860B2 (en) 1999-06-04 2012-06-19 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Methods and compositions for treating primary and secondary tumors of the central nervous system (CNS)
US7345039B2 (en) 1999-06-04 2008-03-18 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Enhancement of effectiveness of 5-fluorouracil in treatment of tumor metastases and cancer
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EP1066830A3 (en) * 1999-06-04 2002-10-16 Ed. Geistlich Söhne Ag Für Chemische Industrie Uses and compositions for treating primary and secondary tumors of the central nervous system (cns)
US6479481B1 (en) 1999-06-04 2002-11-12 Ed. Geistlich Soehne Ag Fur Chemische Industrie Methods and compositions for treating primary and secondary tumors of the central nervous system (CNS)
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US6964959B2 (en) 1999-12-06 2005-11-15 Carter Wallace, Inc. Use of a methylol-containing compound to treat tumors
US6995164B2 (en) 1999-12-06 2006-02-07 Rhode Island Hospital Methods of treating tumors
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US6703413B2 (en) * 1999-12-06 2004-03-09 Rhode Island Hospital Use of taurolidine to treat tumors
US7479505B2 (en) 1999-12-06 2009-01-20 Geistlich Phama Ag Use of taurolidine to treat tumors
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US6521616B2 (en) 1999-12-06 2003-02-18 Rhode Island Hospital, A Lifespan Partner Methods of treating tumors with taurolidine
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EP1797884A3 (en) * 1999-12-06 2010-02-10 Geistlich Pharma AG Use of taurolidine or taurultam for the manufacture of a medicament for the treatment of tumors of the central nervous system
US6641571B2 (en) 2000-01-05 2003-11-04 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Reduction of postoperative complications of cardiopulmonary bypass (CPB) surgery
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EP1208840A3 (en) * 2000-11-28 2003-05-21 Ed Geistlich Söhne AG Für Chemische Industrie Combination of fluorouracil and a methylol transfer agent for the treatment of tumor metastases and cancer
EP1377281A1 (en) * 2001-03-15 2004-01-07 Rhode Island Hospital Taurine compounds
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US6753328B2 (en) 2001-10-01 2004-06-22 Rhode Island Hospital Methods of inhibiting metastases
US8394397B2 (en) 2003-03-28 2013-03-12 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Adhesive antineoplastic compositions
US8236794B2 (en) 2003-09-29 2012-08-07 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Treatment of mesothelioma
WO2008029264A2 (en) * 2006-09-07 2008-03-13 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method of treating bone cancer
WO2008029264A3 (en) * 2006-09-07 2008-09-04 Geistlich Soehne Ag Method of treating bone cancer
EP3028705A1 (en) * 2006-09-07 2016-06-08 Ed. Geistlich Söhne Ag Für Chemische Industrie Treating bone cancer

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JP3465824B2 (en) 2003-11-10
EP0491018A1 (en) 1992-06-24
GB9015108D0 (en) 1990-08-29
JPH05500973A (en) 1993-02-25

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