Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-03-26
2001-07-10
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
Reexamination Certificate
active
06258845
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of cancer biology and biochemistry. More particularly, the present invention is directed to a method of cancer chemotherapy in mammals.
2. Description of Related Art
Mutational activation of the Kirsten (Ki)-ras oncogene is an important genetic alteration in colorectal neoplasia. Ki-ras mutations have been detected in approximately 50 percent of sporadic human colorectal tumors (Vogelstein et al., 1988; Burmer and Loeb, 1989). Ki-ras mutations have been detected in aberrant crypt foci, as well as in adjacent regions of histologically normal mucosa (Losi et al., 1996). These findings suggest that the mutation of Ki-ras may be a relatively early event in the temporal development of colon cancer. Ki-ras also is mutated in chemically-induced rodent tumors, such as the azoxymethane (AOM)-treated rat model, with a frequency similar to that of human cancers (Erdman, 1997; Vivona et al., 1993). Although the role of Ki-ras in tumorigenesis is unclear, activation of this gene has been correlated with deficient apoptosis in human colorectal neoplasms (Ward et al., 1997).
The nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, piroxicam (Reddy et al., 1990; Singh et al., 1994), indomethacin (Narisawa, 1981), and sulindac (Piazza et al., 1997; Rao et al., 1995), effectively inhibit colon carcinogenesis in the AOM-treated rat model. NSAIDs also inhibit the development of tumors harboring an activated Ki-ras (Singh and Reddy, 1995). NSAIDs appear to inhibit carcinogenesis via the induction of apoptosis in tumor cells (Bedi et al., 1995; Lupulescu, 1996; Piazza et al., 1995; Piazza et al., 1997b). A number of studies suggest that the chemopreventive properties of the NSAIDs, including the induction of apoptosis, is a function of their ability to inhibit prostaglandin synthesis (reviewed in DuBois et al., 1996; Lupulescu, 1996; Vane and Botting, 1997). Recent studies, however, indicate that NSAIDs may act through both prostaglandin-dependent and -independent mechanisms (Alberts et al., 1995; Piazza et al., 1997a; Thompson et al., 1995; Hanif, 1996). Sulindac sulfone, a metabolite of the NSAID sulindac, lacks COX-inhibitory activity yet induces apoptosis in tumor cells (Piazza et al., 1995; Piazza et al., 1997b) and inhibits tumor development in several rodent models of carcinogenesis (Thompson et al., 1995; Piazza et al., 1995, 1997a).
Several NSAIDs have been examined for their effects in human clinical trials. A phase IIa trial (one month) of ibuprofen was completed and even at the dose of 300 mg/day, a significant decrease in prostoglandin E
2
(PGE
2
) levels in flat mucosa was seen. A dose of 300 mg of ibuprofen is very low (therapeutic doses range from 1200-3000 mg/day or more), and toxicity is unlikely to be seen, even over the long-term. However, in animal chemoprevention models, ibuprofen is less effective than other NSAIDs. Studies have suggested a beneficial effect of the NSAID, aspirin, on colon cancer incidence, with effects being evident only at a weekly total dose of 1000 mg or greater (Giovannucci et al., 1996). However, three large cohort studies have produced conflicting reports on the beneficial effect of aspirin (Gann et al., 1993; Giovannucci et al., 1996; Greenberg et al., 1993). One group of investigators has recently shown that PGE
2&agr;
can be decreased at a dose between 80 and 160 mg/day. In contrast, another group of investigators have shown no such effect on colon mucosal prostaglandins at these low doses of aspirin, although substantial education of prostaglandins in upper gastrointestinal mucosa was demonstrated. The results of these studies indicate that a dose of aspirin of 80 mg is at the threshold of effect of this agent on colon mucosa.
The NSAID piroxicam is the most effective chemoprevention agent in animal models (Pollard and Luckert, 1989; Reddy et al., 1987), although it demonstrated side effects in a recent IIb trial. A large meta-analysis of the side effects of the NSAIDs also indicates that piroxicam has more side effects than other NSAIDs (Lanza et al., 1995). Sulindac has been shown to produce regression of adenomas in Familial Adenomatous Polyposis (FAP) patients (Muscat et al, 1994), although at least one study in sporadic adenomas has shown no such effect (Ladenheim et al., 1995).
The importance of Ki-ras activation in NSAID-mediated chemoprevention has not yet been determined. NSAIDs induce apoptosis in both colon tumor cell lines and animal tissues, and appear to inhibit Ki-ras activation in tumors, however the activation of Ki-ras has not yet been investigated as a mechanism of NSAID-mediated cytotoxicity. It also is not known if such cytotoxicity is dependent on the anti-inflammatory properties of the NSAIDs. The NSAID sulindac, which also inhibits Ki-ras activation, is metabolized to two different molecules which differ in their ability to inhibit COX, yet both are able to exert chemopreventive effects via the induction of apoptosis. Sulindac sulfone lacks COX-inhibitory activity, and most likely facilitates the induction of apoptosis in a manner independent of prostaglandin synthesis.
&agr;-Difluoromethylornithine (DFMO) is an enzyme-activated, irreversible inhibitor of ornithine decarboxylase (ODC) and causes depletion in the intracellular concentrations of putrescine and its derivative, spermidine (Pegg, 1988). Levels of spermine, which is derived from spermidine, are not as markedly affected by the enzyme inhibition. DFMO was initially synthesized for therapeutic anticancer usage, but it was found not to be an active cytotoxic agent in chemotherapy trials against human cancer (McCann and Pegg, 1992), except perhaps demonstrating moderate activity in the treatment of malignant brain tumors (Levin et al., 1987). In general, the compound was nontoxic, with the significant exception of hearing loss, which was reversible after the drug treatment was discontinued (Meyskens et al., 1986). The onset of the hearing loss could be associated with total cumulative dose (Croghan et al., 1991).
In experimental animal models, DFMO is a potent inhibitor of carcinogenesis that is especially active in preventing carcinogen-induced epithelial cancers of many organs, including those of the colon (Weeks et al., 1982; Thompson et al., 1985; Nowels et al., 1986; Nigro et al., 1987). DFMO acts late in the tumor-promotion phase in animals, but the precise mechanism by which it inhibits the development of polyps and cancers is unknown. Effects on cell transformation, invasion, and angiogenesis by ornithine decarboxylase and polyamines have been reported (Auvinen, 1997); for example, overexpression of ODC enhances cellular transformation and invasion (Kubota et al., 1997).
The combination of DFMO and piroxicam has been shown to have a synergistic chemopreventive effect in the AOM-treated rat model of colon carcinogenesis (Reddy et al., 1990), although DFMO exerted a greater suppressive effect than piroxicam on Ki-ras mutation and tumorigenesis when each agent was administered separately (Singh et al., 1993; Reddy et al., 1990; Kulkami et al., 1992). In one study, administration of DFMO or piroxicam to AOM-treated rats reduced the number of tumors harboring Ki-ras mutations from 90% to 36% and 25% respectively (Singh et al., 1994). Both agents also reduced the amount of biochemically active p21 ras in existing tumors. (Singh et al., 1993).
There remains a need for effective and less toxic methods for treating cancers. Current treatment protocols, especially those for colon cancers and polyps, include tumor resection, chemotherapy and radiation therapy. Colorectal cancer is the second leading cause of death from cancer in The United States.
SUMMARY OF THE INVENTION
Accordingly, it is the object of the present invention to provide a novel method for preventing and/or treating cancer in a patient having an Ki-ras-dependent cancer comprising administering an effective amount of difluoromethylomithine (DFMO) in combination with sulindac
Gerner Eugene W
Meyskens, Jr. Frank L.
Fulbright & Jaworski
Goldberg Jerome D.
The Regents of the University of California
LandOfFree
DFMO and sulindac combination in cancer chemoprevention does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with DFMO and sulindac combination in cancer chemoprevention, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and DFMO and sulindac combination in cancer chemoprevention will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2466574