Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-06-05
2003-09-30
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S025000, C514S283000
Reexamination Certificate
active
06627614
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method for treating disease using a 20(S)-camptothecin and an anthracycline, and more specifically a method for treating disease using a 20(S)-camptothecin and an anthracycline in a sequential therapy.
2. Description of Related Art
A. 20(S)-Camptothecins
20(S)-camptothecin, a plant alkaloid, was found to have anticancer activity in the late 1950's. Wall, M. et al.,
Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata
, J. Am. Chem. Soc. 88: 3888-3890, (1966); Monroe E. Wall et al.,
Camptothecin: Discovery to Clinic
, 803 Annals of the New York Academy of Sciences 1 (1996). These documents, and all documents articles, patents, etc.) cited to herein, are incorporated by reference into the specification as if reproduced fully below. The chemical formula of camptothecin was determined to be C
20
H
16
N
2
O
4
.
20(S)-camptothecin itself is insoluble in water. However, during the sixties and seventies the sodium salt of 20(S)-camptothecin was derived from 20(S)-camptothecin through opening of the lactone ring using a mild base. Clinical trials were then conducted using this hydrosoluble, sodium salt derivative of 20(S)-camptothecin 20(S)-camptothecin Na+), which was administered intravenously. The studies were later abandoned because of the high toxicity and low potency of 20(S)-camptothecin Na
+
. Gottlieb, J. A., et al.,
Preliminary pharmacological and clinical evaluation of camptothecin sodium salt
(
NSC
100880), Cancer Chemother. Rep. 54:461-470 (1979); Muggia, F. M., et al.,
Phase I clinical trials of weekly and daily treatment with camptothecin
(
NSC
100880):
Correlation with clinical studies
, Cancer Chemother. Rep. 56:515-521 (1972); Gottlieb, J. A. et al.,
Treatment of malignant melanoma with camptothecin
(
NSC
100880), Cancer Chemother. Rep. 56:103-105 (1972); and Moertel, C. G., et al.,
Phase II study of camptothecin
(
NSC
100880)
in the treatment of advanced gastrointestinal cancer
, Cancer Chemother Rep. 56:95-101 (1972).
Despite its potential, interest in 20(S)-camptothecin as a therapeutic remained at a low ebb until the mid-1980's. By that time, drug therapies were being evaluated for treating human cancer using human cancer xenograft lines. During these evaluations, human tumors are serially heterotransplanted into immunodeficient, so-called Anude@ mice, and the mice then tested for their responsiveness to a specific drug (Giovanella, B. C., et al.,
Cancer
52(7): 1146 (1983)). The data obtained in these studies strongly support the validity of heterotransplanted human tumors into immunodeficient mammals, such as nude mice, as a predictive model for testing the effectiveness of anticancer agents.
20(S)-camptothecin, and later some of its substituted forms, elicited differential responses in the cell cycle of nontumorigenic and tumorigenic human cells in vitro. Although it is not yet understood why 20(S)-camptothecin and some of its substituted forms are cytostatic for nontumorigenic cells and cytotoxic for tumorigenic cells, the selective toxicity of the compounds against tumorigenic cells in vitro and in vivo was an especially interesting feature of these drugs.
Investigators began to experiment with various substituted forms of 20(S)-camptothecin. Good activity was found when various substitutions were made to the 20(S)-camptothecin scaffold. For example, (9-Amino-20(S)-Camptothecin (9AC) and 10,11-Methylendioxy-20(S)-Camptothecin (10,11 MD) are capable of having high anticancer activity against human colon cancer xenografts. Giovanella, B. C., et al.,
Highly effective topoisomerase
-1
targeted chemotherapy of human colon cancer in xenografts
, Science 246:1046-1048 (1989).
Additionally, 9-nitrocamptothecin (9NC) has shown high activity against human tumor xenograft models. 9NC has a nine position hydrogen substituted with a nitro moiety. 9NC has inhibited the growth of human tumor xenografts in immunodeficient nude mice and has induced regression of human tumors established as xenografts in nude mice with little or no appearance of any measurable toxicity. D. Chatterjee et al.,
Induction of Apoptosis in Malignant and Camptothecin
-
resistant Human Cells
, 803 Annals of the New York Academy of Sciences 143 (1996).
U.S. Pat. No. 5,552,154 to Giovanella et al. disclosed methods of treating specific forms of cancer with water-insoluble 20(S)-camptothecin and derivatives thereof, having the closed-lactone ring intact. In particular, transdermal, oral and intramuscular methods of administration using solutions of water-insoluble 20(S)-camptothecin were disclosed.
Other substituted 20(S)-camptothecin compounds that have shown promise include 7-ethyl-10-hydroxy 20(S)-camptothecin, and other 7, 9, 10, 11-substituted compounds.
B. Anthracyclines
Anthracyclines are commonly known to be highly active antineoplastic agents. Anthracyclines include rhodomycin derivatives, including doxorubicin, duanorubicin, idarubicin, epirubicin, and mitoxantrone, as well as agents such as aclacinomycin A and related compounds.
Anthracyclines are known cytostatic agents, e.g., they inhibit or suppress cell growth and multiplication. Antracyclines act by an incompletely understood mechanism, which includes some antihelicase activity, and have been observed to exert a differentiation-inducing effect.
Anthracyclines, which comprise a four membered anthracycline nucleus attached to a sugar molecule, are clinically important anti-neoplastic agents. Doxorubicin is widely used in treating several solid tumors while daunorubicin and idarubicin are used exclusively for the treating leukemias. Daunorubicin and doxorubicin are identical except for the presence of a hydrogen or hydroxyl at position 14 of the anthracycline ring. Idarubicin, 4-demethoxy-daunorubicin, is a new anthracycline in which the structural modification at position 4 of the chromophore ring increases lipophilicity and half-life.
Anthracyclines bind double stranded DNA by intercalation as has been demonstrated experimentally. Their cytotoxicity largely results from this binding. Human chromosome preparations treated with anthracyclines exhibit the bound drug as defined, orange-red fluorescent bands. If structure of the anthracyclines is modified to reduce intercalative binding of DNA, a decrease or loss of antitumor activity is usually observed. Thus, DNA binding appears critical for anti-neoplastic activity of these drugs.
The specific mechanism of cytotoxicity is not clearly understood. Because inhibition only of DNA and RNA synthesis occurs at high drug concentration only, it is not thought critical to cytotoxicity. Anthracyclines exert a number of cellular physiologic effects, any one or a combination of which may mechanistically effect their cytotoxicity.
By intercalating DNA, anthracyclines can affect many functions of the DNA including DNA and RNA synthesis. Breakage of the DNA strand can also occur. This is believed to mediated either by inhibition of the enzyme DNA Topoisomerase II (hTopII) or by the formation of free radicals. Inhibition of the enzyme hTopII, for example, can lead to a series of reactions leading to double strand breaks in the DNA. Thus the mechanism of action of anthracyclines is complex and at best poorly understood.
As camptothecin inhibits human topoisomerase I (hTopI) which possesses multiple enzymatic activities. It influences the topology of DNA as does hTopII, which is evidenced to be inhibited by the anthracyclines. But hTopI is also capable of phosphorylating proteins essential for mRNA splicing, evidencing hTopI involvement in the RNA splicing process. Inhibitors of hTopI such as camptothecins are therefore important anti-neoplastic pharmacotherapeutic agents.
Because hTopI, a 765-amino-acid nuclear enzyme (Stewart et al. (1996)
J. Biol. Chem
. 271:7593-601) involved in topological changes of DNA structure (Pommier et al. 1998)
Biochim. Biophys. Acta
1400:83-106), plays ke
Chen Shirley
Reamer James H
Super Gen, Inc.
Wilson Sonsini Goodrich & Rosati
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