USE OF TAUROLIDINE AND/OR TAURULTAM FOR THE TREATMENT OF TUMOURS

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: 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 1.5xl0 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. 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 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). 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: 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.

Inventors: MONSON JOHN, MONSON, JOHN
Applicants: GEISTLICH SOEHNE AG, ED GEISTLICH SOEHNE AG FUER CHEMISCHE INDUSTRIE
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61K38, A61P35, C07D285