Topoisomerase II poison and bis-dioxopiperazine derivative...

Details Topoisomerase II poison and bis-dioxopiperazine derivative... Topoisomerase II poison and bis-dioxopiperazine derivative...

1999-03-08

2001-07-24

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S035000, C514S252010, C514S255030, C536S004100, C544S357000, C544S358000

Reexamination Certificate

active

06265385

ABSTRACT:

FIELD OF INVENTION
The present invention relates to the treatment of malignant conditions which are sensitive to topoisomerase II poisons. In particular, the invention relates to a method for selectively killing tumour or metastatic cells within the central nervous system of a large mammal such as a human.
BACKGROUND OF THE INVENTION
Studies concerning patients suffering from primary cancer outside the central nervous system (CNS) show that 20-25% of the patients develop metastasis of the CNS. However, the risk of developing metastases is dependent on the specific cancer form.
The metastatic complications are very often the patient's first symptom of cancer and may give rise to serious neurological complications at a time when the patient is unaffected by the primary cancer.
The treatment of primary cancer and metastasis of the CNS is far from satisfactory. Most measures, whether radiotherapy or chemotherapy, are limited by the fact that the treatment also affects the normal tissue; accordingly, the tolerance of the normal tissue to the specific treatment is of great importance. The most serious side-effect of chemotherapy is myelosuppression.
The target site for cytotoxic drugs differs significantly among cancer drugs. The essential nuclear enzyme topoisomerase II allows the separation of intertwined DNA strands by creating a transient double stranded break in the DNA backbone. This catalytic cycle of topoisomerase II is believed to be the target of some of the most successful antitumour agents used today, e.g. etoposide (VP-16) in the treatment of testicular and small cell lung cancer (2). There is solid evidence that etoposide, as well as a number of other clinically successful antitumour agents such as daunorubicin and doxorubicin (Adriamycin) (28), are active by inhibiting the resealing of the DNA breaks created by topoisomerase II (19, 21). Although the precise cell killing mechanism is unknown, an obligatory step for the cytotoxicity of the topoisomerase II targeting agents is an increase in cleavable complexes between DNA and topoisomerase II (19). This complex mechanism of cell killing is susceptible to drug modulation.
The clinically active DNA intercalating drug, aclarubicin, completely antagonizes the cytotoxicity of topoisomerase II targeting agents such as etoposide, teniposide, m-AMSA, (amsakrin; 4′-(9-acridinylamino)-methanesulfone-m-anisidide) daunorubicin, and oxaunomycin (15, 16, 17). Not only aclarubicin, but also several other DNA binding agents such as ethidium bromide (24), 9-aminoacridines (7, 20), and chloroquine (18) can antagonize the cytotoxicity of topoisomerase II targeting agents. It is believed that these DNA binding drugs inhibit the initial DNA binding step of the enzyme and thereby suppress the interaction between the enzyme, the topoisomerase II targeting drug, and DNA. Recently, more specific interactions with topoisomerase II have been described. Thus, it appears that cation chelating bis-dioxypiperazines may lock topoisomerase II at its magnesium/ATP binding site at the stage of the catalytic cycle where the homodimeric enzyme is thought to be in the form of a closed bracelet surrounding the DNA (22, 23). By locking the enzyme, the bis-dioxopiperazine seems to hinder topoisomerase II poisons from exerting their cytotoxicity. Thus, the bis-dioxypiperazine derivative ICRF-187 (dexrazoxane; (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane) abolishes both DNA breaks and cytotoxicity caused by the topoisomerase II poisons etoposide and daunorubicin (25).
The antagonistic effect of ICRF-187 has been observed on the drug daunorubicin (14), but not on the chemically very similar doxorubicin, and this latter topoisomerase II poison is therefore excluded from the invention. Similarly no antagonism on clerocidin has been found.
SUMMARY OF THE INVENTION
The present invention provides an effective treatment of cancer by utilizing the antagonistic effect of a bis-dioxopiperazine on a topoisomerase II poison.
More specifically, the present invention relates to the treatment of malignant conditions which are sensitive to topoisomerase II poisons wherein the normal tissue is substantially protected from the poison by the bis-dioxopiperazine whereby the malignant conditions can be treated with higher dosages of the topoisomerase II poison.
In particular, the invention relates to a method for selectively killing tumour or metastatic cells within the central nervous system of a large mammal, such as a human. In the following description, the term patient may be used as a synonym for a large mammal.
The method comprises administration, e.g to a human, of an effective CNS-tumour- or metastasis-killing amount of a topoisomerase II poison except doxorubicin together with administration of a bis-dioxopiperazine compound. The non-CNS tissue of the patient is preferentially protected against the toxic action of the topoisomerase II poison by the bis-dioxypiperazine compound whereby increased dosages of the topoisomerase II poison are tolerated compared to the conventional administration of the topoisomerase II poison alone.
Topoisomerase II poisons such as etoposide are usually already used in maximally tolerated doses in the clinic, and therefore, dose increments which otherwise might have overcome drug resistance are not feasible. However, use of an antagonist together with an agonist according to the present invention may give new prospects. However, if such models of manipulation of etoposide effect are to be useful, they should enable significant dose escalations in vivo.
Here it is demonstrated that ICRF-187 in a mouse model markedly antagonizes the toxicity of etoposide in vivo and accordingly carries the prospect of powerful effect regulation.
Furthermore, it has surprisingly been found that when ICRF-187 is used with etoposide in vivo, the normal treatment schedule for etoposide relating to treatment every day in 3 days or in 5 days is not effective. Thus, the simultaneous use of ICRF-187 in the treatment with etoposide involves a completely new approach to the treatment schedule of topoisomerase II poisons.


REFERENCES:
patent: 5242901 (1993-09-01), Speyer et al.
patent: 5587382 (1996-12-01), Krapcho et al.
patent: 2163601 (1972-06-01), None
patent: 0 393 575 (1990-10-01), None
patent: 0409499 (1991-01-01), None
patent: 2 257 430 (1993-01-01), None
patent: WO 86/00812 (1986-02-01), None
patent: WO 92/08460 (1992-05-01), None
patent: 9208460 (1992-05-01), None
patent: 9307873 (1993-04-01), None
Hasinoff et al., “Chemical, Biological and Clinical Aspects of Dexrazoxane and Other Bisdioxopiperazines,”Current Medicinal Chemistry, 5(1), 1-28 (1998).*
Clark et al., “The Clinical Pharmacology of Etoposide and Teniposide,”Clinical Pharmacokinetics, 12, 223-252 (1987).*
Holm et al., “Improved Targeting of Brain Tumors Using Dexrazone Rescue of Topoisomerase II Combined with Supralethal Doses of Etoposide and Teniposide,”Clinical Cancer Research, 4, 1367-1373 (Jun., 1998).*
Chabner, “Anticancer Drugs,” and Grever et al., “Cancer Drug Discovery and Development,”Chapter 18, Introduction and Section 1 inCancer: Principles&Practice of Oncology, Fourth Edition, De Vita, Jr. et al. (eds.), J. B. Lippincott Co, Philadelphia, PA, 1993, only pp. 325-340 supplied.*
Wasserman et al., “Mechanistic Studies of Amsacrine-resistant Derivatives of DNA Topoisomerase II,”Journal of Biological Chemistry, 269(33), 20943-20951 (Aug. 19, 1994).*
Von Hoff et al., “Pharmacokinetics of ICRF-187 in the Cerebrospinal Fluid of Subhuman Primates,”Cancer Treatment Reports, 64(4-5), 734-736 (Apr./May, 1980).*
Ishida et al., “Inhibition of Intracellular Topoisomerase II by Antitumor Bis(2,6-dioxopiperazine) Derivatives: Mode of Cell Growth Inhibition Distinct from that of Cleavable Complex-forming Type Inhibitors,”Cancer Research, 51, 4909-4916 (Sep. 15, 1991).*
Sehested, Maxwell et al., “Antangonistic effect of the cardioprotector (+)-1,2-bis(3, 5-dioxopiperazinyl-1-yl) propane (icrf-187) on dna breaks and cytotoxicity induced by the topoisomerase II directed drugs daunorubici

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