Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-03-06
2003-08-05
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06602910
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of cancer and biology. More particularly, it concerns methods for use of the D-enantiomer of difluoromethylornithine in cancer therapy.
2. Description of Related Art
Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis (Pasic et al., 1997). The two enantiomers of DFMO have been reported to differ in their ability to inhibit ODC, with the L form being more potent then the D enantiomer (Danzin et al., 1987). Although the physiologic functions of polyamines are not completely understood, it is clear that their intracellular concentration is highly regulated and that normal cell growth, replication, differentiation, secretory and repair functions require polyamines (Pegg and McCann, 1982; Oka et al., 1981; Pegg, 1986; Bachrach, 1973; Williams-Ashman and Canellakis, 1979; Thet et al., 1984; Luc and Baylin, 1984). Polyamines have been found in high levels in many tumor cells (Pasic et al., 1997) and support sustained cell growth that is essential for the multistep process of cancer development. In animal models of colon carcinogenesis, inhibition of ODC by DFMO reduces the number and size of colon adenomas and carcinomas (Meyskens and Gerner, 1995). Elevated levels of ODC have also been reported in transitional cell carcinoma of the bladder and the use of DFMO as a treatment for bladder cancer patients has been reported (Messing et al., 1995).
One of the unfortunate side effects of DFMO treatment is disruption of auditory function. Polyamines have been found in the cochlea, but their role in hearing is unknown (Schweitzer et al., 1986). A potential role of polyamines in the cochlea could be to allow interactions with hydrophobic environments, such as those occurring in membranes and they may regulate the flux of inorganic cations (Canellakis et al., 1979). Cochlear function is intimately dependent on the unique electrolytic concentration and positive polarization of the endolymph. Therefore, changes in the levels of polyamines could alter the kinetics of electrolytes that underlie the endocochlear potential and consequently affect cochlear function (Schweitzer et al., 1986).
Two types of ototoxicity are known, a vertigo-like syndrome and hearing loss (Meyskens and Gerner, 1995). As the daily dose of D,L-DFMO increases (0.5 g/m2/day to 3 g/m2/day), the magnitude and incidence of threshold shift increases, and the time until onset of the threshold shift decreases (Pasic et al., 1997). Patients with normal (threshold less than 30 dB) baseline audiograms demonstrate more hearing loss than those with abnormal (threshold greater than or equal to 30 dB) baseline audiograms at the higher frequency levels (Crogham et al., 1991). Both side effects are reversible after drug discontinuation (Meyskens and Gerner, 1995), with recovery of threshold showing no dependence on the magnitude of the threshold shift or the dose of D,L-DFMO that was administered (Pasic et al., 1997).
Development of chemotherapeutic agents with less ototoxic potential is complicated by a lack of dosage data in animal models and by uncertainty over which species are susceptible to DFMO ototoxicity. The route of DFMO administration most commonly employed has been via ingestion of adulterated drinking water. However, accurate quantitation of water intake (and thereby drug dose) has not been carried out. Weight loss is a serious consequence of such DFMO exposure (Meyskens et al., 1995), and it is not clear whether the weight loss results from subjects limiting their intake of contaminated water possibly due to factors such as taste) or from the toxic effect of the drug itself.
The models for DFMO study produce conflicting data. In the guinea pig, D,L-DFMO inhibits ODC activity in cochlear tissue and a significant depletion of cochlear polyamines results (Marks et al., 1991). Along with this, brainstem audiometry shows that treatment by water adulterated with 1% D,L-DFMO produces hearing loss accompanied by damage in the hook and first turn with a loss of hair cells in all rows. Inner hair cells are lost at a greater rate than outer hair cells (OHCs) (Salzer et al, 1990). When the rat is used as the model, the cochlear polyamines are not depleted to a level considered critical for disrupting polyamine-dependent processes in other systems. Auditory thresholds evaluated by brainstem evoked potentials remained unchanged in the D,L-DFMO treated rats (Schweitzer et al., 1986) although only a limited dose range was investigated.
There exists a need for therapeutic compositions and methods of use of those compositions for the treatment of cancer that demonstrate lower toxicities and/or other side effects.
SUMMARY OF THE INVENTION
The present invention concerns a method for preventing and/or treating cancer in a patient comprising administering an effective amount of substantially enriched D enantiomer of difluoromethylornithine (D-DFMO) or an analog thereof to the patient. D-DFMO or an analog thereof is administered at a dose of about 0.05 to about 20.0 gm/M
2
/day. In preferred embodiments, D-DFMO is administered at a dose of about 0.1 to about 2.0 gm/M
2
/day. D-DFMO or an analog thereof may be administered more than once for the treatment and/or prevention of cancer.
The cancer may be bladder cancer, colon cancer, breast cancer, pancreatic cancer, brain cancer, lung cancer, stomach cancer, a blood cancer, skin cancer, testicular cancer, prostate cancer, ovarian cancer, liver cancer, esophageal cancer, and any combination thereof. In preferred embodiments, the cancer is colon cancer, and may include familial adenomatous polyposis. In other preferred embodiments, the cancer is bladder cancer, and may include superficial bladder cancer. Preventing and/or treating cancer in a patient by administration of D-DFMO or an analog thereof can involve resection of a solid tumor. D-DFMO or an analog thereof may be administered prior to the resection or following the resection.
Preventing and/or treating cancer in a patient by administration of D-DFMO or an analog thereof is accomplished by a mechanism selected from inducing apoptosis, inhibiting cell division, inhibiting metastatic potential, reducing tumor burden, increasing sensitivity to chemotherapy or radiotherapy, killing a cancer cell, inhibiting the growth of a cancer cell, inducing tumor regression and any combination thereof.
Administration of D-DFMO or an analog thereof is by a route selected from oral, intravenous, intramuscular, intratumoral, intraperitoneal, intradermal, dermal, nasal, rectal, vaginal, topical, buccal, and intralymphatic administration. In preferred embodiments, DFMO is administered directly to the tumor. D-DFMO or an analog thereof may also be administered systemically, administered into the regional vasculature of the tumor, or administered into the region lymph system of said tumor. In even more preferred embodiments, D-DFMO is administered orally.
Substantially enriched means the D enantiomer comprises at least 60% by weight of the difluoromethylornithine dosage being administered, or at least 70% by weight of the difluoromethylornithine dosage being administered, or at least 80% by weight of the difluoromethylornithine dosage being administered, or at least 90% by weight of the difluoromethylornithine dosage being administered, or at least 95% by weight of the difluoromethylornithine dosage being administered, or at least 97.5% by weight of the difluoromethylornithine dosage being administered, or at least 99% by weight of the difluoromethylornithine dosage being administered. In preferred embodiments, the D enantiomer comprises at least 99.5% by weight of the difluoromethylornithine or analog dosage being administered.
The present invention also concerns a pharmaceutical composition, comprising substantially enriched D enantiomer of difluoromethylornithine (D-DFMO) or an analog thereof together with a pharmaceutically acceptable carrier. The D-DFMO pharmaceutic
Levenson Corey
Shaked Ze'ev
Goldberg Jerome D.
Ilex Oncology, Inc.
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