Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2002-08-13
2003-11-25
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S283000
Reexamination Certificate
active
06653351
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of clinical cancer trials and chemopharmaceuticals. More particularly, it concerns the combined use of eflornithine, lomustine, matulane and vincristine for the treatment of anaplastic gliomas.
2. Description of Related Art
A. Gliomas
Gliomas are a diverse group of brain tumors that arise from normal “glial” cells of the brain and/or their precursor cells. The most important determinant of survival for gliomas is the “grade” of the glioma. Secondary determinants of survival are age at diagnosis, performance status, and extent of surgery. Patients with low-grade gliomas have a protracted natural history with generally long survival times, while those with high grade gliomas are much more difficult to successfully treat and have shorter survival times. All gliomas have specific signs and symptoms that are primarily related to the location and size of the glioma.
The temporal lobe gliomas, for example, may cause seizures, difficulty with speech and/or loss of memory. The frontal lobe gliomas may cause seizures, behavioral changes, weakness of the arms or legs on the opposite side of the body, and/or difficulty with speech. The occipital gliomas may cause loss of vision. The parietal gliomas may cause loss of spatial orientation, diminished sensation on the opposite side of the body, and/or inability to recognize once familiar objects or persons.
Astrocytomas are glioma tumors that arise from brain cells called astrocytes or their precursors. Astrocytes are cells in the central nervous system that support neuronal function. Astrocytomas can be graded by histologic features that signify increasing malignancy into astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme. Anaplastic astrocytoma and glioblastoma multiforme are considered high-grade gliomas while the astrocytoma is considered to be a low-grade glioma. High-grade tumors grow rapidly and can easily infiltrate and spread through the brain. Low-grade astrocytomas can also infiltrate the brain but are usually more localized and grow slowly over a long period of time. High-grade tumors are much more aggressive and require very intense therapy. The majority of astrocytic tumors in children are low-grade, whereas the majority in adults are high-grade. Astrocytomas can occur anywhere in the brain and spinal cord, however the majority are located in the cerebral hemispheres (the top part of the brain).
Oligodendrogliomas are also gliomas. They arise from oligodendrocytes and/or their cell precursors. Normal oligodendrocytes provide myelin, a fatty substance that covers nerve axons in the brain and spinal cord and allows nerves to conduct electrical impulses more efficiently. Oligodendrogliomas are classified as low grade oligodendroglioma (less aggressive) and anaplastic oligodendroglioma (more aggressive). More common than pure oligodendrogliomas are low grade and anaplastic tumors that are a mixture of astrocytoma and oligodendroglioma (“oligoastrocytomas”).
Anaplastic oligodendrogliomas and mixed oligoastrocytomas are more sensitive to cytotoxic chemotherapy than astrocytomas. A high rate of response to the PCV (procarbazine (matulane), CCNU (lomustine), vincristine) chemotherapy has made the use of this regimen, if not the standard of care for these tumors, at least a very common treatment. Additionally, low grade oligodendrogliomas are also sensitive to chemotherapy, and PCV can be used when low grade tumors begin to grow despite prior surgery and radiation therapy.
B. Chemotherapy
In 1983, it was reported that surgery plus radiation therapy and BCNU chemotherapy significantly improved the survival of patients with malignant glioma, as compared to those treated with surgery plus radiation therapy without chemotherapy. In one study, both procarbazine and streptozotocin demonstrated effectiveness similar to that of BCNU. Other studies showed that BCNU alone is as effective as BCNU followed by procarbazine, and that PCNU was no better than BCNU. In some studies the PCV combination was found superior to BCNU for anaplastic gliomas, while in other studies they are considered equivalent.
In addition to controlled survival-based clinical trials, a large number of agents have also been tested in response-based studies in glioma patients. To date, however, no drug has been found to be more effective than the nitrosoureas.
C. DFMO
Difluoromethylomithine (DFMO; eflomithine) is an irreversible inhibitor of omithine decarboxylase (ODC), a key enzyme in mammalian polyamine biosynthesis (Pasic et al, 1997). 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; Pegg, 1986; Bachrach et al., 1973; Williams-Ashman and Canellakis, 1979; Thet et al., 1984; Luk 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 Gemer, 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).
DFMO and its use in the treatment of benign prostatic hypertrophy are described in two patents, U.S. Pat. Nos. 4,413,141, and 4,330,559. U.S. Pat. No. 4,413,141 describes DFMO as being a powerful inhibitor of ODC, both in vitro and in vivo. Administration of DFMO causes a decrease in putrescine and spermidine concentrations in cells in which these polyamines are normally actively produced. Additionally, DFMO has been shown to be capable of slowing neoplastic cell proliferation when tested in standard tumor models. U.S. Pat. No. 4,330,559 describes the use of DFMO and DFMO derivatives for the treatment of benign prostatic hypertrophy. Benign prostatic hypertrophy, like many disease states characterized by rapid cell proliferation, is accompanied by abnormal elevation of polyamine concentrations. The treatment described within this reference can be administered to a patient either orally, or parenterally.
Because DFMO is an effective inhibitor of ODC, some researchers are attempting to use DFMO as part of a conjunctive treatment in combination with other therapeutic agents. For instance, U.S. Pat. No. 4,499,072 describes improving the polyamine-depletion effects of ODC inhibitors (including DFMO) by using interferon in combination with the ODC inhibitor. Additionally, it describes the use of both an ODC inhibitor and interferon in conjunction with a known cytotoxic agent such as methotrexate. U.S. Pat. No. 5,002,879, describe a similar conjunctive therapy in which an ODC inhibitor, preferably DFMO, is used in combination with lymphokine-activated killer (LAK) cells and interleukin-2.
Despite advances in the art, there is a need for effective and improved therapies for anaplastic gliomas.
SUMMARY OF THE INVENTION
Thus, in accordance with the present invention, there is provided a method of treating anaplastic glioma in a subject comprising administering to said subject, in combined amount to effect treatment, a treatment regimen comprising at least one cycle of eflomithine, a hydrazine or triazine alkylating agent, preferably matulane, and a second alkylating agent, preferably a nitrosourea. The treatment may further comprise a tubulin interactive agent, preferably vincristine. Thus, the regimen may comprise eflornithine, matulane and a nitrosourea and, optionally, vincristine. The nitrosourea may be carmustine or, preferably, lomustine. In one aspect of the invention, the treatment regimen comprises at least one cycle of eflornithine, lomustine, matulane and vincristine administration, in combined amount
Board of Regents , The University of Texas System
Fulbright & Jaworski LLP
Reamer James H
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