Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ortho-hydroxybenzoic acid or derivative doai
Reexamination Certificate
2001-04-05
2004-03-09
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ortho-hydroxybenzoic acid or derivative doai
C514S167000
Reexamination Certificate
active
06703380
ABSTRACT:
The present invention relates to the chemoprophylaxis of colorectal cancer with combinations of a cyclooxygenase (COX) inhibitor, vitamin D
3
including analogues and metabolites thereof and/or calcium. In a further aspect the invention relates to a method for reducing the effective dosage of ASA in a chemoprofylactive treatment of colorectal cancer in a human by co-administration with a non toxic dosage of a vitamin D
3
including analogues and metabolites thereof and Ca in the form of a combination dosage. In a still further embodiment the invention relates to the use of a cyclooxygenase (COX) inhibitor, a vitamin D
3
and calcium together with a pharmaceutically acceptable carrier for the preparation of a medicament for preventing the initiation and/or progression of colorectal cancer in a human. The invention also relates to such a pharmaceutical medicament.
Colorectal cancer (CRC) is one of the leading cancer forms in the Western world (1.3 million per year and over 600,000 annual deaths). In Denmark, the incidence is approximately 65 per 100,000 inhabitants and correlates to age. Concurrently with a fall in tobacco smoking in Western industrial countries and an increased life expectancy, CRC is expected to become the most frequent solid cancer over the next decades.
The great majority of CRC cases are sporadic cancers, for which it is not possible to establish a genetic disposition. Effective CRC prevention in well-defined risk groups would have a significant effect on population health.
In the average population the lifetime risk of getting CRC is 6 per cent, and the risk of dying from the disease is 3 per cent (1,2,3). In first-degree relatives of patients with CRC, the risk is several times higher. In rare cases, the CRC disposing factors are hereditary non-polyposis colorectal cancer (HNPCC), where it is possible to establish the presence of mutations in mismatch repair genes, familial adenomatous polyposis (FAP, mutation in the APC gene), or inflammatory bowel diseases (ulcerative colitis and Crohn's disease), these factors accounting for 5 to 15 per cent in all.
There is no doubt that foods are the most important causal factor, including animal proteins and fats, which the Western world is increasingly eating in excess amounts instead of cereals, fruits and vegetables. The incidence of CRC is increasing, but it is only half the magnitude among vegetarians as among meat-eaters (4). The progress made during the last decades within surgical techniques, adjuvant treatment, etc, has not lowered mortality to any mentionable degree. CRC screening means tracing cancers at an early stage and removing intestinal polyps, but so far, however, studies have not shown screening to reduce the incidence. The overall five-year survival in Denmark is approximately 30 per cent and depends on the stage at the time of diagnosis. Approximately 25 per cent of the patients have disseminated cancer at the time of diagnosis and are beyond a cure. Three fourths of CRC patients undergo surgery intended to cure; nevertheless, 50 per cent of these patients die within five years because of recurrence.
With the choices and results of treatment known today, only effective prophylaxis will be able to reduce CRC morbidity and mortality (3,5) in a decisive manner.
In recent years, focus is very much on cancer prophylaxis, in acknowledgement of the fact that surgery mostly does not suffice as the only modality and that most cytotoxic regimens are ineffective against solid tumours.
The term chemoprophylaxis covers the use of pharmacologically active, non-cytotoxic agents or naturally occurring nutrients that protect against the emergence and development of clones of mutated, malignant cells.
In 1994, to analyse existing data and to initiate new studies, the National Cancer Institute, USA, established a Chemopreventive Branch. The NCI-CB has concluded that CRC is an attractive target for cancer chemoprophylaxis, since it is a frequent cancer with a high mortality. However, no acceptable treatment is available.
A well-defined multistage carcinogenesis has been mapped with well-defined precursors in the form of colorectal adenomas, and the groups at risk are also well defined.
Some studies have pointed to an inverted correlation between the individual intake of non-steroid anti-inflammatory drugs (NSAID), and of calcium and vitamin D
3
and the risk of developing CRC. The studies in question are animal experimental models of colorectal carcinogenesis, prospective studies of patients with FAP and epidemiological studies taking the form of retrospective case-control studies and prospective cohort and interventional studies (6-17). In conclusion, 21 of 23 epidemiological studies have shown that regular use of NSAIDs reduces the risk of CRC by up to 50 per cent (18). However, data are not clear regarding dosage and duration of use. The most frequently studied drugs are acetylsalicylic acid, sulindac, piroxicam and indomethacin.
A few review articles and editorials have been published which find the results interesting, but existing data have neither led to any recommendations proper nor proved any clinical significance (12). This is primarily because of the well-known undesirable effects of NSAIDs and the acknowledgement that the strongest evidence of the effect of these agents does not exist, ie, prospective, randomised double-blind trials in human populations.
The American Cancer Society has concluded that current data from epidemiological, clinical, pharmacological and toxicological studies show that acetylsalicylic acid protects against CRC development (13), and the FDA is currently assessing whether acetylsalicylic acid taken alone should be approved as chemoprophylaxis of CRC, or whether further phase III studies will be necessary.
Animal experimental data draw a promising picture of pharmacologically active drugs that, with different mechanisms of action, appear to be effective chemoprophylactic agents. However, individual epidemiological studies of calcium and vitamin D (or milk products) in relation to CRC are inconsistent. Out of 13 studies of calcium (nine case-control and four cohort studies), eight show a significant inverse correlation, three studies report insignificant correlation, whereas two fail to show any correlation.
Out of five epidemiological studies (three cohort studies and two case-control studies) of the impact of vitamin D on the CRC risk, two show a significant inverse correlation, whereas the rest have no significance.
The sequence of epithelium-adenoma-carcinoma is a process taking many years (5 to 10 years). CRC differs from many other cancers in as much as mutations in cell-cycle regulating genes and gene products are rarely seen. CRC is characterised by mutations in critical tumour suppressor genes (APC, DCC, p53, MCC) and oncogenes (K-ras) and upregulation in growth factors (especially the EGF-family) and enzymatic activity (especially cyclooxygenase).
In spite of CRC being a frequent cancer form, its incidence is only 65 per 100,000 inhabitants, and a clinical-controlled study with the endpoints being invasive cancer and cancer-related deaths would require enrolment of tens of thousands individuals, and it would run for several decades and require astronomical financial resources. Healthy individuals do not feel impelled to participate in scientific studies including long-term medicine intake, and the results of any such studies would be subject to confounding.
Over 95 per cent of CRC develop from adenomas, which are accepted CRC precursors in scientific studies of humans and in animal experiments. Other biomarkers include genomic changes (mutations, etc), aberrant crypt foci (ACF), ornithine decarboxylase activity, cyclooxygenase activity and the prostaglandin level in mucosa, which are used as intermediary endpoints.
Colorectal carcinogenesis and Calcium:
In the Western world, the daily average intake of calcium is substantially below the recommended dietary allowance (RDA) of 800 to 1200 mg/day, increasing to 1500 mg/day for the elderly. In Western countries, each
Colotech A/S
Goldberg Jerome D.
Hunton & Williams LLP
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