Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-09
2002-05-21
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06391911
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
In an aspect, the invention relates to treatment of cancer, more particularly to coadministration of lucanthone and radiation for treatment of cancer.
2. Description of the Related Art
Management of patients with central nervous system (CNS) cancers remains a formidable task. Conventional chemotherapy administered systemically as a monotherapy tends not to be very effective because conventional chemotherapeutic agents tend not to reach portions of the CNS in effective amounts, primarily because of the blood-brain barrier. For example, etoposide and actinomycin D, two commonly used oncology agents that inhibit topoisomerase II, fail to cross the blood-brain barrier in useful amounts. Radiation therapy improves median survival. P. L. Kornblith et al, Chemotherapy for Malignant Gliomas, J. Neurosurg. 68: 1-17 (1988). This document, and all others cited to in this patent, is incorporated by reference as if reproduced fully herein. The benefit of radiotherapy, however, is limited by several factors. Although intrinsic radioresistance and rapid cellular proliferation may contribute to therapeutic inefficacy, dose escalation has not yet yielded superior results and is limited by the radiation tolerance of normal brain as reported by O. M. Solazar et al.,
High Dose Radiation Therapy in the Treatment of Malignant Gliomas: Final Report
, Int. J. Radial. Oncol. Biol. Phys., 3: 1733-1740 (1979).
Combinations of chemotherapy and radiation have been experimented with in the treatment of CNS cancers. The additional use of nitrosoureas adds a modest gain for selected patients. M. D. Walker,
Randomized Comparisons of Radiotherapy and Nitrosoureas for the Treatment of Malignant Glioma After Surgery
, N. Eng. J. Med., 303: 1323-1329 (1980). U.S. Pat. No. 5,637,085 to Cardinale, with an issue date of Jun. 10, 1997, discloses a method and composition for intralesional therapy of solid cancer tumors, and especially brain tumors, comprising delivering a compound of a 1,2,4-benzotriazine oxide contained in a biodegradable, slow release polymer and subjecting the cancer tumors to irradiation therapy.
A problem with combining chemotherapy and radiation is that the blood-brain barrier interferes with transport of the chemotherapeutic agent into areas of the CNS, just as in monotherapy using chemotherapeutic agents. This reduces effectiveness of such therapies. For instance, compounds such as etoposide may be included in many multidrug protocols in medical oncology. However, etoposide crosses the blood-brain barrier poorly, thereby restricting its use in patients with central nervous system (CNS) lesions. The rapid induction of secondary leukemia in 1%-5% of patients is an obvious disadvantage of etoposide. Despite development of a number of different protocols, the overall survival of patients with CNS lesions such as glioblastoma multiforme, treated with surgery, radiation and chemotherapy, remains a dismal ten per cent.
There is therefore a need for a combination of chemotherapeutic agents and radiation that addresses the problems noted above.
SUMMARY OF THE INVENTION
In an aspect, the invention relates to a method of treating a cancer of the central nervous system in a host comprising administering radiation to the host, and administering lucanthone to the host; wherein the radiation and lucanthone are administered in amounts effective to cause the arrest or regression of the cancer of the central nervous system in the host. In another aspect, the invention relates to a method of treating tumors of the central nervous system comprising inducing base damage to a tumor cell's DNA, and inhibiting excision repair of that damage by providing lucanthone to the cell.
DETAILED DESCRIPTION OF THE INVENTION
The inventor has unexpectedly discovered that lucanthone may be advantageously administered, together with administration of radiation, in the treatment of cancers of the central nervous system, wherein the radiation and lucanthone are administered in amounts effective to cause the arrest or regression of the cancer of the central nervous system in the host.
Part of lucanthone's particular advantage in treating central nervous system cancers is that the inventor has established lucanthone's surprising ability to cross the blood-brain barrier in test animals, such as mice and rats. The inventor also has inferred its surprising ability to cross the barrier in humans. Therefore, lucanthone may be administered in physiologically tolerable amounts so as to have activity in the central nervous system, whereas other chemotherapeutic or radiosensitizing agents may not be so administered.
Lucanthone is a chemotherapeutic or radiosensitizing intercalating agent. For convenience, the term lucanthone is taken to include lucanthone proper, as 1-diethylaminoethylamino-4-methyl-10-thiaxanthenone, together with physiologically tolerated derivatives, analogs, and salts thereof. Such physiologically tolerated derivatives, analogs, and salts include, but are not limited to, Hycanthone, indazole analogues of lucanthone, and other analogs such as those disclosed in Thomas Corbett et al., Antitumor Activity of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxo-9H-thiaxanthen-4-yl]methyl]methanesulfonamide (WIN33377) and analogues, Exp. Opin. Invest. Drugs 3:1281-1292 (1994); and Mark P. Wentland et al., Anti-solid Tumor Efficacy and Preparation of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxo-9H-thiaxanthen-4-yl]methyl]methanesulfonamide (WIN33377) and Related Derivatives, Bioorg. & Med. Chem Lett. 4:609-614 (1994).
Lucanthone, which has been marketed as Nilodin or Miracil D, has been used as a treatment for schistomiasis. Lucanthone has been known to have an cytotoxic or cytostatic effect on growing cells. The enhanced joint lethal action of lucanthone and ionizing radiation in cells may be accounted for by the production of DNA double strand breaks (DSB) in cleavable complexes because of lucanthone's inhibition of topoisomerase II, combined with the DSB induced by radiation alone. R. Bases, DNA Intercalating Agents as Adjuvants in Radiation Therapy,
Int J Radiat Oncol Biol Phys
4:345-346 (1978) (editorial); R. E. Bases et al., Topoisomerase Inhibition by Lucanthone, an Adjuvant in Radiation Therapy,
Int J Radiat Oncol Biol Phys
37:1133-1137 (1997).
Topoisomerase II may also be implicated in the mechanism of radiation induced DSB by an additional mechanism. When DNA bases are damaged by ionizing radiation, they are first removed by cells' base excision repair enzymes, which first remove the damaged bases (by a glycosylase) and leave abasic sites. Removal of abasic sites is achieved in the second step, performed by endonucleases that cause strand scission and leave 3′ OH groups, which are required acceptors in DNA repair synthesis. Subsequent steps include removal of 5′ phosphate groups at the sites of excised bases, followed by gap filling by DNA polymerase &bgr;, which inserts appropriate replacement nucleotides. DNA ligase completes repair by sealing in the replacement nucleotides.
If the abasic sites are not removed they could continue to act as endogenous topoisomerase II poisons, thereby promoting (lethal) DSB. P. S. Kingma et al., Abasic Sites Stimulate Double-stranded DNA Cleavage Mediated by Topoisomerase II: DNA Lesions as Endogenous Topoisomerase II Poisons.
J Biol Chem
270:21441-21444 (1995).
It seems likely that topoisomerase II inhibitors, like lucanthone and Actinomycin D, which induce DNA double strand breaks by inhibiting topoisomerase II, might also enhance DNA double strand breaks in cell DNA by interfering with the removal of abasic sites in the second step of base excision repair described above. If so, the endogenous abasic site topoisomerase II poisons would persist in the DNA, leaving them in place to cause more double strand breaks over a longer time, thereby leading to a more than additive lethal effect. Unpublished data of the inventor
Goldberg Jerome D.
Kenyon & Kenyon
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