Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-01-20
2002-11-26
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06486144
ABSTRACT:
The present invention is concerned with a method for the treatment of tumours and in particular, with a method for the treatment of tumours in the liver. The invention is also concerned with compositions suitable for such treatment.
BACKGROUND OF THE INVENTION
Hepatoma (primary liver cancer) is one of the commonest causes of cancer death in the world with an estimated incidence of 1 million cases per year worldwide (Lencioni R and Bartolozzi C. The Cancer Journal, Vol 10, pp1-6). There is a considerable variation in its incidence with it being the most common in Asian countries. although it is now of increasing importance in the West. There are currently few effective treatment options available. Untreated, the average survival in this condition is of the order of 3 months. Liver resection may allow 5 year survival in approximately 40% of cases but very few patients are eligible for such treatment. Systemic chemotherapy has been of very limited value in the treatment of primary hepatic cancer, and attempts have consequently been made to deliver pharmacologically active agents directly to the liver using the technique of transarterial chemoembolisation (TAE). TAE combines the selective delivery of agents to hepatic tumours vascularized by the hepatic artery and thus their concentration in the tumour, with the concept of causing embolisation of the tumour and hence necrosis by ischemia. A wide range of chemotherapy agents have been delivered in this way, including doxorubicin, epirubicin and cisplatin (Choi, J. Cancer Control, Vol 3, pp407-413, 1996). Frequently, chemotherapeutic agents are emulsified with or dissolved in the contrast agent Lipiodol, which is an iodised poppy seed oil fatty acid ethylester. Uptake of iodised oil into tumours is thought to prolong contact of the chemotherapeutic agent with tumour, and the radioopaque nature of the medium enables progress of the infusion to be monitored by radiography.
Vitamin D is an isoprenoid compound made up of activated 5-carbon units. The most abundant form of vitamin D is vitamin D
3
, or cholecalciferol. Vitamin D
3
arises from biosynthesis of 7-dehydrocholesterol, an intermediate in cholesterol biosynthesis. Vitamin D
3
is metabolised in the liver to 25-hydroxycholocalciferol [25(OH)D
3
] which is a major form of Vitamin D circulating in the blood compartment. 25(OH)D
3
is converted by the kidney to produce two principal dihydroxylated metabolites, namely, 1.25-dihydroxycholecalciferol [1.25(OH)
2
D
3
] and 24,25-dihydroxycholocalciferol [24R,25(OH)
2
D
3
].
1.25(OH)
2
D
3
is the most biologically active naturally occurring form of vitamin D
3
and is transported in the bloodstream to its major site of action in the mucosal cells of the intestine, where calcium absorption is stimulated. Thus vitamin D
3
may be regarded as a prohormone because it is converted to a metabolite that acts analogously to a steroid hormone. It regulates calcium and phosphorous metabolism particularly in the synthesis of the inorganic matrix of bones.
Therapeutically, 1.25(OH)
2
D
3
and certain other analogues of Vitamin D
3
are used to counteract deleterious effects of dietary deficiency of Vitamin D (rickets), or in the treatment of diseases characterised by abnormalities in the synthesis of or response to Vitamin D such as hypophosphatemic vitamin D-resistant rickets and renal osteodystrophy (renal rickets). A further use in the calcification-related disease osteoporosis is distinct from assuring vitamin D nutritional adequacy. Here, the rationale is directly to suppress parathyroid function and reduce bone turnover (Goodman & Gilman, The Pharmacological basis of Therapeutics. Pub. 1992, The McGraw Hill Companies Inc). Finally, a recent use of Vitamin D
3
analogues is in the treatment of the cutaneous disease psoriasis.
Experimental studies have shown that Vitamin D
3
receptors are present on a range of cell types and so the understanding has arisen that the Vitamin D endocrine system is involved in the modulation of a number of fundamental cellular processes not directly related to calcium homeostasis (Pols, HAP et al, J Steroid Biochemistry, Vol 37, pp873-876, 1990). Included amongst the cells bearing Vitamin D
3
receptors are a number of malignant tissues or cell lines derived from tumours. The presence of receptors on some cancer cells has been shown to have a functional significance in a number of cases, and the literature contains reports of Vitamin D
3
and analogues being able to inhibit the proliferation of melanoma, osteosarcoma and breast carcinoma cells (Deluca HF and Ostrem V, Advances in Experimental Medicine and Biology, Vol 206, pp413-429, 1986) colon adenocarcinoma cells (Cross HS et al Journal of Nutrition, Vol 127 Suppl. pp2004-2008, 1995) and hepatic tumour cells (Tanaka Y et al, Biochem Pharmacol vol 38 pp449-453, 1989).
This effect in vitro has given rise to the hope that Vitamin D
3
and analogues could be used in the treatment of cancers. Vitamin D
3
compounds are listed among “unconventional cancer therapies” (British Columbia Cancer Agency publication; 600 West 10th Ave, Vancouver, BC, Canada), and clinical trials have attempted to show an effect. Unfortunately, attempts to use naturally occurring analogues of Vitamin D
3
such as 1.25(OH)
2
D
3
have not been associated with the successful treatment of cancer and indeed have rarely been attempted. This is due in large part to the observation that for growth reduction of cancer cells to be caused by Vitamin D
3
, supraphysiological concentrations are needed (Pols et al-ibid). The consequence of this is that before anti-tumour properties of the treatment can be expressed, the effects of Vitamin D
3
on calcium homeostasis are expressed to an excessive and dangerous degree, leading to life-threatening toxicity from hypercalcaemia.
In an attempt to overcome this problem, and to disassociate the hypercalcaemic effect of Vitamin D
3
from its actions on cell differentiation, the pharmaceutical industry has expended much effort on the search for synthetic analogues that are devoid of an effect on calcium metabolism, and might therefore be useful for the treatment of cancer or other diseases. This approach has met with some limited success. For example, the analogue Calcipotriol has been synthesized which contains a 22-23 double bond, a 24(S)-hydroxy functional group, and carbons 25-27 incorporated into a cyclopropane ring. This compound has receptor affinity similar to that of 1.25(OH)
2
D
3
, but it is less than 1% as active as 1.25(OH)
2
D
3
in regulating calcium metabolism. Calcipotriol has been studied extensively as a potential treatment for psoriasis (Goodman & Gilman, The Pharmacological Basis of Therapeutics Pub McGraw Hill, 1992). However, despite its reduced effect on calcium metabolism, calcitriol is used topically in order to avoid systemic hypercalcaemia. Examples have also been disclosed of synthetic Vitamin D analogues claimed to be useful for the treatment of tumours which have reduced effects on calcium metabolism (U.S. Pat. No. 4,891,364, Jan 2 1990). Also, attempts have been made to treat certain cancers locally. Thus, Bower M et al treated breast cancer topically with Calcipotriol (Lancet vol 337: No 8743 pp701-702). Of the 19 patients treated, only 3 showed a significant response and 1 a minimal response. Moreover, even though this synthetic analogue has a drastically reduced effect on calcium metabolism (vide supra) and even though the treatment was locally restricted to skin around breast cancer lesions, still 2 of the 19 patients became hypercalcaemic during treatment.
Thus, despite the interesting findings of basic researchers and the intensive efforts of the pharmaceutical industry, the application of Vitamin D compounds to cancer therapy has not been successful. The key limitation has been either an inherent lack of activity, or the low therapeutic index (ratio of effective dose to toxic dose) of Vitamin D
3
which has made its use so difficult.
SUMMARY OF THE INVENTION
We have found that, surprisingly, r
Criares Theodore J.
MRC Holdings Pty Limited
Nixon & Vanderhye
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