EP0491018A1 - Use of taurolidine and/or taurultam for the treatment of tumours - Google Patents
Use of taurolidine and/or taurultam for the treatment of tumoursInfo
- Publication number
- EP0491018A1 EP0491018A1 EP91911804A EP91911804A EP0491018A1 EP 0491018 A1 EP0491018 A1 EP 0491018A1 EP 91911804 A EP91911804 A EP 91911804A EP 91911804 A EP91911804 A EP 91911804A EP 0491018 A1 EP0491018 A1 EP 0491018A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- taurolidine
- taurultam
- tumours
- treatment
- administered
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention se rapporte à un procédé de traitement ou de prophylaxie de tumeurs chez des sujets mammifères, selon lequel on administre une dose active de taurolidine et/ou de taurultame à un sujet mammifère atteint ou présentant un risque de formation tumorale.The present invention relates to a method for the treatment or prophylaxis of tumors in mammalian subjects, according to which an active dose of taurolidine and / or taurultam is administered to a mammalian subject affected or at risk of tumor formation.
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:
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9015108 | 1990-07-09 | ||
| GB909015108A GB9015108D0 (en) | 1990-07-09 | 1990-07-09 | Chemical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0491018A1 true EP0491018A1 (en) | 1992-06-24 |
Family
ID=10678847
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP91911804A Withdrawn EP0491018A1 (en) | 1990-07-09 | 1991-07-08 | Use of taurolidine and/or taurultam for the treatment of tumours |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0491018A1 (en) |
| JP (1) | JP3465824B2 (en) |
| GB (1) | GB9015108D0 (en) |
| WO (1) | WO1992000743A1 (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19606897C2 (en) * | 1996-02-13 | 2002-08-29 | Geistlich Soehne Ag | Means for preventing the spread of tumor cells and the development of trocar metastases in open and laparoscopic surgery of malignant tumors |
| US20030027818A1 (en) * | 2001-04-03 | 2003-02-06 | Redmond H. Paul | Treatment of cancers |
| 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 |
| 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) |
| GB9716219D0 (en) * | 1997-07-31 | 1997-10-08 | Geistlich Soehne Ag | Prevention of metastases |
| US20020098164A1 (en) * | 2000-10-27 | 2002-07-25 | Redmond H. Paul | Treatment of tumor metastases and 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 |
| 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 |
| EP1797884B1 (en) * | 1999-12-06 | 2013-09-11 | Geistlich Pharma AG | Taurolidine or taurultam for use in the treatment of tumors of the prostate, colon, lung and for the treatment of recurrent glioblastoma multiforme |
| AU784539B2 (en) * | 1999-12-06 | 2006-04-27 | Geistlich Pharma Ag | Methods of treating tumors |
| CN100519525C (en) | 1999-12-06 | 2009-07-29 | 葛兰素集团有限公司 | Aromatic sulfones and their medical use |
| US6641571B2 (en) | 2000-01-05 | 2003-11-04 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Reduction of postoperative complications of cardiopulmonary bypass (CPB) surgery |
| CA2363973C (en) * | 2000-11-28 | 2009-03-10 | Ed. Geistlich Sohne Ag Fur Chemische Industrie | Enhancement of effectiveness of 5-fluorouracil in treatment of tumor metastases and cancer |
| US6812251B2 (en) * | 2001-03-15 | 2004-11-02 | Rhode Island Hospital | Taurine compounds |
| JP5280603B2 (en) | 2001-10-01 | 2013-09-04 | ガイストリッヒ ファーマ アーゲー | Methods for metastasis inhibition |
| AU2004201264B2 (en) | 2003-03-28 | 2009-12-24 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Adhesive Antineoplastic Compositions |
| JP5043294B2 (en) | 2003-09-29 | 2012-10-10 | エー・デー・ガイストリヒ・ゾーネ・アクチェンゲゼルシャフト・フュール・ヒェーミシェ・インダストリー | How to treat mesothelioma |
| US20100040667A1 (en) * | 2006-09-07 | 2010-02-18 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Method of treating bone cancer |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8328073D0 (en) * | 1983-10-20 | 1983-11-23 | Geistlich Soehne Ag | Chemical compounds |
-
1990
- 1990-07-09 GB GB909015108A patent/GB9015108D0/en active Pending
-
1991
- 1991-07-08 WO PCT/EP1991/001269 patent/WO1992000743A1/en not_active Application Discontinuation
- 1991-07-08 EP EP91911804A patent/EP0491018A1/en not_active Withdrawn
- 1991-07-08 JP JP51135891A patent/JP3465824B2/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9200743A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3465824B2 (en) | 2003-11-10 |
| GB9015108D0 (en) | 1990-08-29 |
| JPH05500973A (en) | 1993-02-25 |
| WO1992000743A1 (en) | 1992-01-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19920215 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): DE ES FR GB IT |
|
| 17Q | First examination report despatched |
Effective date: 19940201 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 19941102 |