Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
2000-11-28
2004-01-13
Kunz, Gary (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
C514S169000, C514S171000, C514S177000, C514S012200, C530S351000, C530S828000
Reexamination Certificate
active
06676934
ABSTRACT:
The present invention relates to a composition. In particular the present invention relates to a pharmaceutical composition—and to a class of compounds particularly useful in or as said composition.
Cancer remains a major cause of mortality in most Western countries. So far, evidence suggests that oestrogens are the major mitogens involved in promoting the growth of tumours in endocrine-dependent tissues, such as the breast and endometrium. Although plasma oestrogen concentrations are similar in women with or without breast cancer, breast tumour oestrone and oestradiol levels are significantly higher than in normal breast tissue or blood. In situ synthesis of oestrogen is thought to make an important contribution to the high levels of oestrogens in tumours and therefore specific inhibitors of oestrogen biosynthesis are of potential value for the treatment of endocrine-dependent tumours.
Over the past two decades, there has been considerable interest in the development of inhibitors of the aromatase pathway which converts the androgen precursor androstenedione to oestrone. However, there is now evidence that the oestrone sulphatase (“E1-STS”) pathway, i.e. the hydrolysis of oestrone sulphate (“E1S”) to oestrone (“E1”), as opposed to the aromatase pathway, is the major source of oestrogen in breast tumours. This theory is supported by a modest reduction of plasma oestrogen concentration in postmenopausal women with breast cancer treated by aromatase inhibitors, such as aminoglutethimide and 4-hydroxyandrostenedione and also by the fact that plasma E1S concentration in these aromatase inhibitor-treated patients remains relatively high. The long half-life of E1S in blood (10-12 h) compared with the unconjugated oestrogens (20 min) and high levels of steroid sulphatase activity in liver and, normal and malignant breast tissues, also lend support to this theory.
Singh et al (1997 J Steroid Biochem Mol Biol 61: 185-192), report that the major source of pro-inflammatory cytokines, such as TNF-&agr; and IL-6 within breast tumours is not well understood but it is thought that tumour infiltrating macrophages and lymphocytes might play a role.
Singh et al (ibid) report that the release of cytokines, such as IL-6 by tumour cells is also associated with enhanced aromatase activity in breast tissue adjacent to the tumour. Singh et al (ibid) also report that both TNF-&agr; and IL-6 inhibit the growth of MCF-7 breast cancer cells in vitro. In addition, TNF-&agr; has an inhibitory effect on aromatase activity measured in cultured MCF-7 breast cancer cells. Apparently, these results contrast with the marked stimulatory effect that TNF-&agr; has on fibroblasts derived from normal and malignant breast tissues (Macdiarmaid et al 1994 Molec. Cell Endoc. 106: 17-21). In addition, when TNF-&agr; is combined with IL-6, the inhibitory effect on aromatase activity is enhanced. The synergistic inhibitory effect of IL-6 and TNF-&agr; on aromatase activity in MCF-7 cells also contrasts to the synergistic stimulatory effect that these cytokines have on oestrone sulphatase and oestradiol dehydrogenase activities in these cells.
Singh et al (ibid) also report that a significant reduction in aromatase activity is observed when conditioned media (CM) from monocytes and lymphocytes of an immunosuppressed kidney transplant patient is added to fibroblast cultures from normal breast cells compared with CM from breast cancer cells. These results suggest that the reduced incidence of breast cancer in immunosuppressed kidney transplant patients could result from reduced cytokine production and thus decreased stimulation of oestrogen synthesis.
Previous studies have also shown that where CM from cultured breast cancer cells stimulates aromatase activity, this CM also stimulates the activities of two main enzymes, that is oestrone sulphatase and oestradiol dehydrogenase which are also involved in breast tumour oestrogen synthesis.
Thus, there appears to be a co-ordinated mechanism for regulating the synthesis of oestrogen within breast tumours that is controlled by cytokines. However, it has been postulated that any in vivo stimulatory effect of cytokines in inhibiting tumour growth may be outweighed by their stimulatory effect on enzyme activity associated with oestrogen synthesis (Duncan and Reed 1995 J Steroid Biochem Molec Biol 55:565-572).
Singh et al (ibid) state that while cytokines such as TNF-&agr; and IL-6 have been shown to play an important role in regulating the activities of enzymes involved in oestrogen synthesis, it is likely that other cytokines and mediators of the inflammatory response are capable of modulating oestrogen synthesis in normal and malignant breast tissue.
Thus, cancer therapies developed so far have included blocking the action or synthesis of hormones to inhibit the growth of hormone-dependent tumours. However, more aggressive chemotherapy is currently employed for the treatment of hormone-independent tumours.
Hence, the development of a pharmaceutical for anti-cancer treatment of hormone dependent and/or hormone independent tumours, yet lacking some or all of the side-effects associated with chemotherapy, would represent a major therapeutic advance.
In fact, Singh et al (ibid) state that “by understanding the complex mechanisms which govern oestrogen synthesis, it should be possible to devise better preventative and therapeutic strategies” against cancers—especially breast cancer.
The present invention seeks to provide a composition suitable for use in the treatment of cancers and, especially, breast cancer.
According to a first aspect of the present invention there is provided a composition comprising i) a compound comprising a sulphamate group (“a sulphamate compound”); and ii) a biological response modifier.
According to a second aspect of the present invention there is provided the use of a composition according to the present invention in the manufacture of a medicament to prevent and/or inhibit tumour growth.
According to a third aspect of the present invention there is provided the use of a composition according to the present invention in the manufacture of a medicament to do any one or more of: prevent or suppress glucose uptake by a tumour; prevent and/or inhibit tumour angiogeneis; disrupt microtubules; induce apoptosis.
According to a fourth aspect of the present invention there is provided the use of a sulphamate compound comprising a steroidal component and an oxyhydrocarbyl group (“oxyhydrocarbyl steroidal sulpharnate compound”) in the manufacture of a medicament to do any one or more of: prevent or suppress glucose uptake by a tumour; prevent and/or inhibit tumour angiogeneis; disrupt microtubules; induce apoptosis.
According to a fifth aspect of the present invention there is provided the composition of the present invention for use in medicine.
According to a sixth aspect of the present invention there is provided a method of treatment comprising administering to a subject in need of treatment a composition according to the present invention.
According to a seventh aspect of the present invention there is provided a method of treatment comprising administering to a subject in need of treatment a composition according to the present invention or an oxyhydrocarbyl steroidal sulphamate compound according to the present invention in order to prevent or suppress glucose uptake by a tumour; and/or prevent and/or inhibit tumour angiogeneis; and/or disrupt microtubules; and/or induce apoptosis.
According to an eighth aspect of the present invention there is provided a kit comprising a part i) containing a compound comprising a sulphamate group (“a sulphamate compound”); and a part ii) containing a biological response modifier. The parts of the kit may be independently held in one or more containers—such as bottles, syringes, plates, wells, blister pack etc.
The present invention is advantageous in that it provides a composition suitable for use in the treatment of cancers and, especially, breast cancer.
In addition, the present invention is advantageous in that it provides a
Lloyd Potter Barry Victor
Reed Michael John
Frommer Lawrence & Haug
Kowalski Thomas J.
Kunz Gary
Seharaseyon Jegatheesan
Sterix Limited
LandOfFree
Pharmaceutical composition with tumor necrosis factor A and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical composition with tumor necrosis factor A and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical composition with tumor necrosis factor A and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3257609