JPH07501818A - Colorectal cancer treatment - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Colorectal cancer treatment Background of the invention The present invention provides a method for administering topotecan to humans suffering from colorectal cancer. characterized by administering an effective amount of a water-soluble camptothecin-like compound such as The present invention relates to a method for treating colorectal cancer in humans.

The structure of the DNA helix in eukaryotic cells is similar to that of cellular organs. atus) must be unraveled in order to use its genetic material as a template. It imposes a kind of topolon-like problem. Separation of DNA strands occurs during DNA replication and It is fundamental to cellular processes such as transcription and transcription. Eukaryotic DNA is converted into chromosomal proteins Therefore, as it is organized into chromatin, the ends are confined and the strands have a topological cannot be solved without the help of enzymes that change For many years, the complexity along the DNA spiral The progression of transcription or replication releases the twisted strands that occur during these processes. It has been recognized that this is facilitated by a pivot point.

Topoisomerases have the ability to change DNA topology in eukaryotic cells It is an enzyme that They are important for important cellular functions and cell proliferation .

There are two types of topoisomerase in eukaryotic cells, type I and type II.

Topoisomerase ■ is a single enzyme with a molecular weight of approximately 100,000. The enzyme is , binds to DNA, induces a transient single-strand break, and unwinds the double-stranded helix (or The cut is then resealed before being dissociated from the DNA strand.

Calcium is a water-insoluble alkaloid produced by trees endemic to China and India. Mbutotenone and other congeners of its 2.3 inhibit topoisomerase ■ It is the only compound known to have

Cambutotenone and other topoisomerase I inhibitor congeners are associated with lack of clinical efficacy, unacceptable dose-limiting toxicity, unpredictable toxicity, poor water solubility, and/or Attractive for clinical drug development as a cell lytic agent due to unacceptable shelf-life stability It wasn't proven to be powerful.

Thus, topoisomerases that avoid the aforementioned undesirable camptothecin characteristics -ase I inhibitors and related topoisomerase II inhibitory congeners are required. topotecan or any water-soluble camptothecin analog compound is a DN that satisfies such requirements. It is a specific inhibitor of A. toboisomerase.

Summary of the invention The present invention provides a method for administering water-soluble Cambutotenone-like compounds to humans suffering from colorectal cancer. The present invention relates to a method for treating colorectal cancer in humans, comprising administering an effective amount. do.

The present invention provides for administering an effective amount of topotecan to a human suffering from colorectal cancer. The present invention also relates to such characterized methods for treating colorectal cancer in humans.

Detailed description of the invention The term "water-soluble cambutotenone analog" was filed on November 2, 1988. U, S, P 5.004. 758 (incorporated herein by reference) means a compound. Any water-soluble Cambutotenone analog (its pharmaceutical (including acceptable salts, hydrates and solvates) and the water-soluble cambu Comprised of a totenone analog and an inert pharmaceutically acceptable carrier or diluent. Preparation of oral and parenteral pharmaceutical compositions according to U, S, P 5.004.758. Disclosed in the scope. Publication number EP 0321 122 on June 21, 1989 European Patent Application No. 88311366.4, published as (incorporated herein) have the same extensive disclosure. Preferred water-soluble cambu Totenne neck-like compound has the formula [In the formula, a) X is hydroxy, R is trimethylammoniummethyl, b ) X is hydroxy, R is N-methylpiperazinylmethyl, c) X is hydroxy, R is N-methylanilinomethyl, d) X is hydroxy, R is cyclohexylaminomethyl, and e) R is N,N-dimethylaminoethyloxymethyl, f) X is hydroxy and R is cyclobropylaminomethyl; g) X is hydroxy; R is morpholinomethyl; h) X is hydroxy; , R is aminomethyl, l) X is hydroxy, R is J) X is hydroxy and R is dimethylaminomethyl ].

Topotecan is the most preferred water-soluble camptothecin analog. Specification When used in the formula, the word "topotecan"

(S)-9-dimethylaminomethyl-10-hydroxycamptothecin and its pharmaceutically acceptable salts, hydrates or solvates.

The chemical name of topotecan is (S)-10[(dimethylamino)methyl]-4-ethyl Leu4.9-hydroxy-IH-pyrano[3°,4':6.7]indolizino [1,2-bl quinolone-3,14(4H,12H)-dione.

Topotecan is water soluble due to the presence of a basic side chain at position 9 that forms salts with acids. . Preferred salt forms of topotecan include hydrochloride, acetate, and methanesulfonate. Examples include phosphate salts. Alkaline hydrolysis of E-ring lactone of tobotecan The alkali metal salt forms of carboxylade prepared are soluble, such as the sodium salt. Salt is also produced.

Preparation of tobotecan (including its pharmaceutically acceptable salts, hydrates and solvates) , and from topotecan and an inert pharmaceutically acceptable carrier or diluent. The preparation of oral and parenteral pharmaceutical compositions according to U.S.P. 5.004.758 Extensively disclosed. Publication number EP O321122 on June 21, 1989 Identical extensive disclosure to European Patent Application No. 88311366.4 published as There is an indication.

The present invention provides a method for administering water-soluble camptothecin-like compounds to humans suffering from colorectal cancer. The present invention relates to a method for treating colorectal cancer in humans, comprising administering an effective amount. do. One preferred embodiment of the invention provides for administering topotecotherapy to humans suffering from colorectal cancer. Such a method for treating colorectal cancer in humans, comprising administering an effective amount of Regarding the law.

As used herein, the term "colorectal cancer" refers to cancer of the colon and/or rectum. means adenocarcinoma.

As used herein, the term "colorectal cancer treatment" refers to the growth of colorectal cancer cells. It means to inhibit reproduction. Preferred such treatments regress tumor growth, That is, it reduces measurable tumor size. Most preferably such treatment causes complete tumor regression. Most preferably, such treatment involves the visible colon It is started immediately after surgical removal of rectal cancer.

The term "administration" means parenteral or oral administration. "Parenteral" means intravenous , meant for subcutaneous and intramuscular administration.

As used herein, "an effective amount of a water-soluble cambutotenone analog" and The term "effective amount of topotecan" refers to a treatment that results in the treatment of colorectal cancer. means unit. The actual preferred therapeutic unit will depend on, among other things, the mode of administration, the Individual formulations of water-soluble cambutotenon analogues (e.g., topotecan), It will likely vary according to the mode given and the individual host treated. predetermined conditions The optimal therapeutic unit for U, S, P 5.00 and the information provided herein is 4°758, using conventional therapeutic unit determination tests. can be determined by a person skilled in the art using Publication number EP 0 on June 21, 1989 European Patent Application No. 88311366.4 published as 321122 There is the same extensive disclosure.

Commonly used treatments for parenteral administration of water-soluble camptothecin analogs The unit is about 0.05 to about 25.0% per body surface area II2 per day for about 1 to 5 consecutive days. It is 0119. More preferably, the treatment units used are daily for about 5 consecutive days. Approximately 10 to 25 rice grains per 1/2 body surface area. Most preferably used The therapeutic unit administered is about 1.5 to about 1.5 to about 200 mg/day of body surface area per day for about 5 consecutive days. It is 2T19. Preferably, the initial dosing schedule and patient's normal tissue at least once at intervals of about 7 days to about 28 days (from the start date of treatment), depending on the treatment. The treatment unit is repeated. Most preferably, the treatment unit is repeated based on tumor response. Keep repeating.

Preferably, parenteral administration is short-term (e.g. 30 minutes) or long-term (e.g. 24 minutes). time) by intravenous infusion. More preferably, topotecan is administered in a 30 minute intravenous infusion. Therefore, it is administered.

At this time, please be sure to check if the polisher has not been treated beforehand or has received light preliminary treatment. The most preferred parenteral treatment unit to be used with Can is short-term therapy for 5 consecutive days. Topotecan 15/2 body surface area per day administered by intravenous infusion The initial therapeutic unit would be mg. If the patient suffers from this initial unit of drug-related effects. After sufficient recovery, an additional dose of 20 topotecan per 11 body surface areas per day Therapeutic units were administered by short-term intravenous infusion for 5 consecutive days and were determined based on tumor response. should be repeated.

At this time, it is used together with topotecan for patients who have undergone thorough preliminary treatment. The most preferred parenteral treatment unit is administration by short-term intravenous infusion for 5 consecutive days. The initial therapeutic unit is 10 doses of topotecan per 1.2 body surface areas per day. I think that the. After the addict has fully recovered from this initial dose of drug-related effects, the daily allowance An additional treatment unit of 15 units of topotecan per 10,000 body surface area was given for 5 consecutive days. administered by short-term intravenous infusion, such therapeutic units are based on tumor response. Should be carried back.

Commonly used therapeutic units for oral administration of water-soluble camptothecin analogues approximately 10 to approximately 50.0 per 112 body surface areas per day for approximately 1 to 5 consecutive days. Shoulder 7. More preferably, the therapeutic units used are per day for about 5 consecutive days. from about 1.5 to about 5,019 per 2 parts of body surface area. Preferably, the therapeutic unit depending on the initial dosing schedule and recovery of the patient's normal tissues (starting treatment). (from the first day) at least once at intervals of about 7 days to about 28 days. most preferred The treatment unit continues to be repeated based on tumor response.

Clinical drug information Topotecan is currently undergoing Phase I clinical studies. The following medical information is supplied to the floor house Delivery Means - Vial containing 5 mg (base) along with Mannitol 100 do. The pH is adjusted to 3.0 with HCr/NaOH. Freeze-dried powder is pale yellow It's a color. Intact vials should be stored under refrigeration (2-8°C).

Solution Preparation - 9 vials were reconstituted with 2 ml Sterile Water for Injection (USP) and each m l is topotecan 2.5 mv and mannitol (USP) 50 mv as base Contains 9. Topotecan is diluted in buffered solution for solubility and stability Do not use or mix with it.

Stability - Shelf life monitoring of intact vials continues. Disposable freeze drying The dry dosage form does not contain an antimicrobial preservative, so the reconstitution solution is It is recommended that it be discarded 8 hours after initial application. Plastics stored at room temperature 5% Dextrose Injection (USP) (-D5W-) or 09% in Kubag 002 Shoulder 9/11 and Q, 1 in Sodium Chloride Injection (USP) (“NS”) Dilution of the reconstitution solution to a concentration of mg, ml gave the following stability results: Percentage of initial tobotecan remaining in the solution D5W 0 100.00 1 00.006 99.29 99.68 24 102.30 98.16 48 101.98 97.91 NS 0 100.00 100.006 98.58 97.71 24 96.01 98.30 48 102.03 98.35 Topotecan diluted in saline (10 μg/ml or 500 μq/ml) or topotecan diluted in dextrose (6,7 μg 7 ml or 330 μg μg/wing I) for 24 hours with a recovery rate of at least 95%. Stable in g-bag) should be diluted in P) (preservative free) and 3 Administered over 0 minutes. Therapeutic doses are kept under refrigeration and protected from light. should be used within 24 hours.

use One person with adenocarcinoma of the colon that is antigenic to standard preliminary treatments for colon cancer of human patients by continuous intravenous infusion over a period of 24 hours per liter of body surface area. A treatment unit consisting of intravenous administration of topotecan 165 was performed. This treatment unit , weekly, repeated at least 4 times to date, with at least 50% tumor coverage. A retreat was observed at the station, and this retreat lasted for at least four weeks.

Claims (1)

[Claims] 1. For people with colorectal cancer, there are formulas ▲mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, a) X is hydroxy and R is trimethylammoniummethyl; b) X is hydroxy and R is N-methylpiperazinylmethyl; c) X is hydroxy and R is N-methylanilinomethyl; d) X is hydroxy, R is cyclohexylaminomethyl, or e) is hydroxy and R is N,N-dimethylaminoethyloxymethyl Ruka, f) X is hydroxy and R is cyclopropylaminomethyl, or g ) X is hydroxy and R is morpholinomethyl; or h) X is hydroxy. roxy, R is aminomethyl, or i) X is hydroxy, R is cyanomethyl or j) X is hydroxy and R is dimethyl is characterized by administering an effective amount of a compound represented by Such a method of treating colorectal cancer in humans. 2. 2. The method of claim 1, wherein the colorectal cancer is adenocarcinoma of the colon. 3. 2. The method of claim 1, wherein the colorectal cancer is adenocarcinoma of the rectum. 4. 2. The method of claim 1, wherein the administration is oral. 5. 2. The method of claim 1, wherein the administration is parenteral. 6. The treatment unit used is 1 m2 of body surface area per day for about 1 to about 5 consecutive days. 6. The method of claim 5, wherein the amount is from about 0.5 to about 25.0 mg per day. 7. The treatment units used are approximately 1 m2 of body surface area per day for approximately 5 consecutive days. 7. The method of claim 6, wherein the amount is 1.0 to about 2.5 mg. 8. The treatment units used are approximately 1 m2 of body surface area per day for approximately 5 consecutive days. 8. The method of claim 7, wherein the amount is 1.5 to about 2 mg. 9. 6. The treatment unit is repeated at least once at intervals of about 7 days to about 28 days. Method described. 10. Claims in which the treatment unit is repeated at least once at intervals of about 7 days to about 28 days. 7. The method described in 7. 11. Claims in which the therapeutic unit is revisited at least once at intervals of about 7 days to about 28 days. 8. The method described in 8. 12. 5. The method of claim 4, wherein the administration is via short-term or long-term intravenous infusion. 13. 13. The method of claim 12, wherein the administration is via a 30 minute intravenous infusion. 14. 13. The method of claim 12, wherein the administration is via 24 hour intravenous infusion. 15. The treatment unit used is 1 m of body surface area per day for about 1 to about 5 consecutive days. 6. The method of claim 5, wherein the amount is from about 1.0 to about 50.0 mg per 2. 16. The treatment units used are per m2 of body surface area per day for approximately 5 consecutive days. 16. The method of claim 15, wherein the amount is about 1.5 to about 5.0 mg. 17. Claims in which the treatment unit is repeated at least once at intervals of about 7 days to about 28 days. 15. The method described in 15. 18. Claims in which the treatment unit is repeated at least once at intervals of about 7 days to about 28 days. 16. The method described in 16. 19. 2. The method of claim 1, wherein the compound is topotecan. 20. 13. The method of claim 12, wherein the compound is topotecan.