EP0572563A1 - Treatment of esophageal cancer - Google Patents
Treatment of esophageal cancerInfo
- Publication number
- EP0572563A1 EP0572563A1 EP92908199A EP92908199A EP0572563A1 EP 0572563 A1 EP0572563 A1 EP 0572563A1 EP 92908199 A EP92908199 A EP 92908199A EP 92908199 A EP92908199 A EP 92908199A EP 0572563 A1 EP0572563 A1 EP 0572563A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hydroxy
- course
- compound
- topotecan
- therapy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- This invention relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the water soluble camptothecin analog class, such as topotecan.
- the structure of the DNA helix within eukaryotic cells imposes certain topological problems that the cellular apparatus must solve in order to use its genetic material as a template.
- the separation of the DNA strands is fundamental to cellular processes such as DNA replication and transcription. Since eukaryotic DNA is organized into chromatin by chromosomal proteins, the ends are constrained and the strands cannot unwind without the aid of enzymes that alter topology. It has long been recognized that the advancement of the transcription or replication complex along the DNA helix would be facilitated by a swivel point which would relieve the torsional strain generated during these processes.
- Topoisomerases are enzymes that are capable of altering DNA topology in eukaryotic cells. They are critical for important cellular functions and cell proliferation. There are two classes of topoisomerases in eukaryotic cells, type I and type II.
- Topoisomerase I is a monomeric enzyme of approximately 100,000 molecular weight. The enzyme binds to DNA and introduces a transient single-strand break, unwinds the double helix (or allows it to unwind) , and subsequently reseals the break before dissociating from the DNA strand. Camptothecin, a water-insoluble alkaloid produced by trees indigenous to China and India, and a few other congeners thereof, are the only class of compounds known to inhibit topoisomerase I.
- Camptothecin and other topoisomerase I inhibiting congeners have not proven to be attractive for clinical drug development as cytolytic agents because of lack of clinical efficacy, unacceptable dose- limiting toxicity, unpredictable toxicity, poor aqueous solubility, and/or unacceptable shelf life stability.
- topoisomerase I inhibiting agents which avoid the aforementioned undesirable features of camptothecin and related topoisomerase I inhibiting congeners.
- Topotecan or any compound of the water soluble camptothecin analog class, is a specific -inhibitor of DNA topoisomerase I which fulfills such need.
- This invention relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the water soluble camptothecin analog class.
- This invention also relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of topotecan.
- a compound of the water soluble camptothecin analog class is meant any compound claimed in U.S. Patent Number 5,004,758, the entire disclosure of which is hereby incorporated by reference.
- the preparation of any compound of the water soluble camptothecin analog class (including pharmaceutically acceptable salts, hydrates and solvates thereof) as well as the preparation of oral and parenteral pharmaceutical compositions comprising a compound of the water soluble camptothecin analog class and an inert, pharmaceutically acceptable carrier or diluent, is extensively described in U.S. Patent Number 5,004,758. The same extensive description is found in European Patent Application Number 88311366.4, published on June 21, 1989 as
- Preferred compounds of the water soluble camptothecin analog class include those compounds of the formula:
- 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 and R is cyclohexylaminomethyl; e) X is hydroxy and R is N,N- dimethylaminoethyloxymethy1/ f) X is hydroxy and R is cyclopropylaminomethy1; g) X is hydroxy and R is morpholinomethyl; h) X is hydroxy and R is aminomethyl; and i) X is hydroxy and R is cyanomethyl; and j) X is hydroxy and R is dimethylaminomethyl or any pharmaceutically acceptable salts, hydrates and solvates thereof.
- Topotecan is the most preferred compound of the water soluble camptothecin analog class.
- Topotecan is water-soluble by virtue of the presence of the basic side-chain at position 9 which forms salts with acids.
- Preferred salt forms of topotecan include the hydrochloride salt, acetate salt and ethanesulfonic acid salt.
- a alkali metal salt form of the carboxylate formed on alkaline hydrolysis of the E-ring lactone of topotecan would also yield a soluble salt, such as the sodium salt.
- topotecan including pharmaceutically acceptable salts, hydrates and solvates thereof
- oral and parenteral pharmaceutical compositions comprising topotecan and an inert, pharmaceutically acceptable carrier or diluent
- European Patent Application Number 88311366.4 published on June 21, 1989 as Publication Number EP 0 321 122.
- This invention relates to a method of treating esophageal cancer in a human afflicted therewith which
- One preferred aspect of this invention relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of topotecan.
- esophageal cancer cancer of the esophagus .
- treating esophageal cancer is meant the inhibition of the growth of esophageal cancer cells.
- treatment also leads to the regression of tumor growth, i.e., the decrease in size of a measurable tumor.
- such treatment leads to the complete regression of the tumor.
- parenteral is meant intravenous, subcutaneous and intramuscular administration.
- effective amount of a compound of the water soluble camptothecin analog class and “effective amount of topotecan” as used herein is meant a course of therapy which will result in treating esophageal cancer. It will be appreciated that the actual preferred course of therapy will vary according to, inter alia, the mode of administration, the particular formulation of a compound of the water soluble camptothecin analog class (such as topotecan) being utilized, the mode of administration and the particular host being treated.
- the course of therapy generally employed is from about 0.5 to about 2 5 25.0 mg/m of body surface area per day for about one to about five consecutive days. More preferably, the course of therapy employed is from about 1.0 to about
- 2 10 therapy employed is from about 1.5 to about 2 mg/m of body surface area per day for about five consecutive days.
- the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval (from the date of initiation of therapy)
- the parenteral administration will be any suitable parenteral administration.
- the parenteral administration will be any suitable parenteral administration.
- the topotecan will be administered by a 30 minute intravenous infusion.
- 25 preferred course of parenteral therapy to be employed with topotecan for a previously non-treated or lightly pretreated patient is an initial course of therapy of
- course of therapy of 1.5 mg of topotecan/m of body surface area per day is administered by short intravenous infusion for five consecutive days, such course of therapy to be repeated based on tumor response.
- the course of therapy generally employed is from about 1.0 to about 2 50.0 mg/m of body surface area per day for about one to five consecutive days. More preferably, the course of
- 2 therapy employed is from about 1.5 to about 5.0 mg/m of body surface area per day for about five consecutive days.
- the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval (from the date of initiation of therapy) depending upon the initial dosing schedule and the patient's recovery of normal tissues. Most preferably, the course of therapy continues to be repeated based on tumor response.
- Topotecan is currently undergoing Phase I clinical investigation.
- the following pharmaceutical information is being supplied to the clinicians:
- Topotecan diluted in saline (10 ug/ml or 500 ug/ml) or dextrose (6.7 ug/ml or 330 ug/ml) is stable in a hang-bag for 24 hours with at least 95% recovery.
- Treatment dose The treatment dose is to be diluted in a final volume of 150 ml of Sodium Chloride Injection, USP (without preservatives) and administered over a 30 minute period.
- the treatment dose is to be kept under refrigeration and protected from light and it is to be used within 24 hours.
- One human patient with metastatic esophageal cancer who was refractory to at least one previous chemotherapeutic regimen with a compound or compounds other than a water soluble camptothecin analog, received a course of therapy comprising intravenous
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Traitement du cancer de l'oesophage chez l'être humain, comprenant l'administration d'une quantité efficace d'un composé de la classe analogue de la camptothécine soluble dans l'eau.Treatment of esophageal cancer in humans, comprising the administration of an effective amount of a compound of the water-soluble class of camptothecin.
Description
TREATMENT OF ESOPHAGEAL CANCER
BACKGROUND OF THE INVENTION
This invention relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the water soluble camptothecin analog class, such as topotecan.
The structure of the DNA helix within eukaryotic cells imposes certain topological problems that the cellular apparatus must solve in order to use its genetic material as a template. The separation of the DNA strands is fundamental to cellular processes such as DNA replication and transcription. Since eukaryotic DNA is organized into chromatin by chromosomal proteins, the ends are constrained and the strands cannot unwind without the aid of enzymes that alter topology. It has long been recognized that the advancement of the transcription or replication complex along the DNA helix would be facilitated by a swivel point which would relieve the torsional strain generated during these processes.
Topoisomerases are enzymes that are capable of altering DNA topology in eukaryotic cells. They are critical for important cellular functions and cell proliferation. There are two classes of topoisomerases in eukaryotic cells, type I and type II.
Topoisomerase I is a monomeric enzyme of approximately 100,000 molecular weight. The enzyme binds to DNA and introduces a transient single-strand break, unwinds the double helix (or allows it to unwind) , and subsequently reseals the break before dissociating from the DNA strand.
Camptothecin, a water-insoluble alkaloid produced by trees indigenous to China and India, and a few other congeners thereof, are the only class of compounds known to inhibit topoisomerase I. Camptothecin and other topoisomerase I inhibiting congeners have not proven to be attractive for clinical drug development as cytolytic agents because of lack of clinical efficacy, unacceptable dose- limiting toxicity, unpredictable toxicity, poor aqueous solubility, and/or unacceptable shelf life stability.
Therefore, there is a need for topoisomerase I inhibiting agents which avoid the aforementioned undesirable features of camptothecin and related topoisomerase I inhibiting congeners. Topotecan, or any compound of the water soluble camptothecin analog class, is a specific -inhibitor of DNA topoisomerase I which fulfills such need.
SUMMARY OF THE INVENTION This invention relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the water soluble camptothecin analog class.
This invention also relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of topotecan.
DETAILED DESCRIPTION OF THE INVENTION By the term "a compound of the water soluble camptothecin analog class" is meant any compound claimed in U.S. Patent Number 5,004,758, the entire disclosure of which is hereby incorporated by reference. The preparation of any compound of the water soluble camptothecin analog class (including pharmaceutically acceptable salts, hydrates and solvates thereof) as well as the preparation of oral and parenteral pharmaceutical compositions comprising a compound of the water soluble
camptothecin analog class and an inert, pharmaceutically acceptable carrier or diluent, is extensively described in U.S. Patent Number 5,004,758. The same extensive description is found in European Patent Application Number 88311366.4, published on June 21, 1989 as
Publication Number EP 0 321 122, the entire disclosure of which is hereby incorporated by reference. Preferred compounds of the water soluble camptothecin analog class include those compounds of the formula:
wherein: 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 and R is cyclohexylaminomethyl; e) X is hydroxy and R is N,N- dimethylaminoethyloxymethy1/ f) X is hydroxy and R is cyclopropylaminomethy1; g) X is hydroxy and R is morpholinomethyl; h) X is hydroxy and R is aminomethyl; and i) X is hydroxy and R is cyanomethyl; and j) X is hydroxy and R is dimethylaminomethyl or any pharmaceutically acceptable salts, hydrates and solvates thereof. Topotecan is the most preferred compound of the water soluble camptothecin analog class. By the term
"topotecan" as used herein is meant the compound of the
SUBSTITUTESHEET
formula:
(S)-9-dimethylaminomethyl-10-hydroxycamptothecin and any pharmaceutically acceptable salt, hydrate or solvate thereof. Topotecan's chemical name is (S)- 10 [ (dimethylamino)methyl]-4-ethyl-4, 9-dihydroxy-lH- pyrano[3',4 • :6,7] indolizino [1, 2-b]quinolone- 3,14 (4H, 12H)-dione.
Topotecan is water-soluble by virtue of the presence of the basic side-chain at position 9 which forms salts with acids. Preferred salt forms of topotecan include the hydrochloride salt, acetate salt and ethanesulfonic acid salt. A alkali metal salt form of the carboxylate formed on alkaline hydrolysis of the E-ring lactone of topotecan would also yield a soluble salt, such as the sodium salt.
The preparation of topotecan (including pharmaceutically acceptable salts, hydrates and solvates thereof) as well as the preparation of oral and parenteral pharmaceutical compositions comprising topotecan and an inert, pharmaceutically acceptable carrier or diluent, is extensively described in U.S. Patent Number 5,004,758. The same extensive description is found in European Patent Application Number 88311366.4, published on June 21, 1989 as Publication Number EP 0 321 122.
This invention relates to a method of treating esophageal cancer in a human afflicted therewith which
SU
comprises administering to such human an effective amount of a compound of the water soluble camptothecin analog class. One preferred aspect of this invention relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of topotecan.
By the term "esophageal cancer" as used herein is meant cancer of the esophagus .
By the term "treating esophageal cancer" as used herein is meant the inhibition of the growth of esophageal cancer cells. Preferably such treatment also leads to the regression of tumor growth, i.e., the decrease in size of a measurable tumor. Most preferably, such treatment leads to the complete regression of the tumor.
By the term "administering" is meant parenteral or oral administration. By "parenteral" is meant intravenous, subcutaneous and intramuscular administration. By the term "effective amount of a compound of the water soluble camptothecin analog class" and "effective amount of topotecan" as used herein is meant a course of therapy which will result in treating esophageal cancer. It will be appreciated that the actual preferred course of therapy will vary according to, inter alia, the mode of administration, the particular formulation of a compound of the water soluble camptothecin analog class (such as topotecan) being utilized, the mode of administration and the particular host being treated. The optimal course of therapy for a given set of conditions can be ascertained by those skilled in the art using conventional course of therapy determination tests in view of the information set out herein, as well as the information outlined in U.S. Patent Number 5,004,758. The same information is found in European Patent Application Number 88311366.4, published on June 21, 1989 as Publication Number EP 0
SUBSTITUTE SHEET
321 122 .
For parenteral administration of a compound of the water soluble camptothecin analog class, the course of therapy generally employed is from about 0.5 to about 2 5 25.0 mg/m of body surface area per day for about one to about five consecutive days. More preferably, the course of therapy employed is from about 1.0 to about
2 2.5 mg/m of body surface area per day for about five consecutive days. Most preferably, the course of
2 10 therapy employed is from about 1.5 to about 2 mg/m of body surface area per day for about five consecutive days. Preferably, the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval (from the date of initiation of therapy)
15 depending upon the initial dosing schedule and the patient's recovery of normal tissues. Most preferably, the course of therapy continues to be repeated based on tumor response.
Preferably, the parenteral administration will
20 be by short (e.g., 30 minute) or prolonged (e.g., 24 hour) intravenous infusion. More preferably, the topotecan will be administered by a 30 minute intravenous infusion.
At this time, it is believed that the most
25 preferred course of parenteral therapy to be employed with topotecan for a previously non-treated or lightly pretreated patient is an initial course of therapy of
2 1.5 mg of topotecan/m of body surface area per day administered by short intravenous infusion for five
30 consecutive days. When the patient has recovered sufficiently from the drug-related effects of this initial course, an additional course of therapy of 2.0
2 mg of topotecan/m of body surface area per day is administered by short intravenous infusion for five
35 consecutive days, to be repeated based on tumor response.
At this time, it is believed that the most
preferred course of parenteral therapy to be employed with topotecan for a heavily pretreated patient is an
2 initial course of therapy of 1.0 mg of topotecan/m of body surface area per day administered by short intravenous infusion for five consecutive days. When the patient has recovered sufficiently from the drug- related effects of this initial course, an additional
2 course of therapy of 1.5 mg of topotecan/m of body surface area per day is administered by short intravenous infusion for five consecutive days, such course of therapy to be repeated based on tumor response.
For oral administration of a compound of the water soluble camptothecin analog class, the course of therapy generally employed is from about 1.0 to about 2 50.0 mg/m of body surface area per day for about one to five consecutive days. More preferably, the course of
2 therapy employed is from about 1.5 to about 5.0 mg/m of body surface area per day for about five consecutive days. Preferably, the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval (from the date of initiation of therapy) depending upon the initial dosing schedule and the patient's recovery of normal tissues. Most preferably, the course of therapy continues to be repeated based on tumor response. Clinical Pharmaceutical Information
Topotecan is currently undergoing Phase I clinical investigation. The following pharmaceutical information is being supplied to the clinicians:
How supplied - As a vial containing 5 mg (of the base) with 100 mg mannitol. The pH is adjusted to 3.0 with HCl/NaOH. Lyophilized powder is light yellow in color. Intact vials should be stored under refrigeration (2-8 degrees Centigrade) .
Solution Preparation -When the 5 mg vial is reconstituted with 2 ml of Sterile Water for Injection,
USP, each ml will contain 2.5 mg of topotecan as the base and 50 mg of mannitol, USP. Topotecan must not be diluted or mixed with buffered solutions because of solubility and stability considerations.
Stability - Shelf life surveillance of the intact vials is ongoing. Because the single-use lyophilized dosage form contains no antibacterial preservatives, it is advised that the reconstituted solution be discarded eight hours after initial entry into the vial. Futher dilutions of the reconstituted solution to concentrations of 0.02 mg/ml and 0.1 mg.ml in 5% Dextrose Injection, USP, ("D5W") or 0.9% Sodium Chloride Injection, USP, ("NS") in plastic bags stored at room temperature yielded the following stability results:
Percentage of Initial Topotecan Remaining in Solution
Concentration Diluent Time (hra. Q.Q2 mg/ml Q.l mg/ml
D5W 0 100.00 100.00
6 99.29 99.68
24 102.30 98.16
48 101.98 97.91
NS 0 100.00 100.00
6 98.58 97.71
24 96.01 98.30
48 102.03 98.35
Topotecan diluted in saline (10 ug/ml or 500 ug/ml) or dextrose (6.7 ug/ml or 330 ug/ml) is stable in a hang-bag for 24 hours with at least 95% recovery.
Treatment dose - The treatment dose is to be diluted in a final volume of 150 ml of Sodium Chloride Injection, USP (without preservatives) and administered over a 30 minute period. The treatment dose is to be kept under refrigeration and protected from light and it is to be used within 24 hours.
Utility
One human patient with metastatic esophageal
cancer, who was refractory to at least one previous chemotherapeutic regimen with a compound or compounds other than a water soluble camptothecin analog, received a course of therapy comprising intravenous
2 administration of 1.5 mg of topotecan/m of body surface area per day for five consecutive days. This course of therapy was repeated at least two to three times at twenty-eight day intervals (from the date of initiation of therapy) for a total of at least three to four treatments. Tumor size regression was evaluated by physical measurement of the affected lymph nodes. Tumor size regression was observed following the first course of therapy of the above-outined treatment regimen. This clinically significant response was maintained at least through the third to fourth treatment.
Claims
1. A method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the formula:
wherein: - - . a) X is hydroxy and R is trimethylammoniummethy1; b) X is hydroxy and R is N- methylpiperazinyImethy1; c) X is hydroxy and R is N-methy1anilinomethyl; d) X is hydroxy and R is cyclohexylaminomethyl; e) X is hydroxy and R is N,N- dimethylaminoethyloxymethyl; f) X is hydroxy and R is cyclopropylaminomethyl; g) X is hydroxy and R is morpholinomethyl; h) X is hydroxy and R is aminomethyl; i) X is hydroxy and R is cyanomethyl; or j) X is hydroxy and R is dimethylar.inomethyl or any pharmaceutically acceptable salts, hydrates and solvates thereof.
2. The method of Claim 1 wherein the administration is oral.
3. The method of Claim 1 wherein the administration is parenteral .
4. The method of Claim 3 wherein the course of
2 therapy employed is from about 0.5 to about 25.0 mg/m
SUBSTITUTESHEET of body surface area per day for about one to about five consecutive days.
5. The method of Claim 4 wherein the course of
2 therapy employed is from about 1.0 to about 2.5 mg/m of body surface area per day for about five consecutive days.
6. The method of Claim 5 wherein the course of
2 therapy employed is from about 1.5 to about 2 mg/m of body surface area per day for about five consecutive days .
7. The method of Claim 4 wherein the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval .
8. The method of Claim 5 wherein the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval .
9. The method of Claim 6 wherein the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval.
10. The method of Claim 2 wherein the administration is via short or long intravenous infusion.
11. The method of Claim 10 wherein the administration is via a 30 minute intravenous infusion.
12. The method of Claim 10 wherein the administration is via a 24 hour intravenous infusion.
13. The method of Claim 3 wherein the course of therapy employed is from about 1.0 to about 50.0 2 mg/m of body surface area per day for about one to about five consecutive days.
14. The method of Claim 13 wherein the course
2 of therapy employed is from about 1.5 to about 5.0 mg/m of body surface area per day for about five consecutive days.
15. The method of Claim 13 wherein the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval .
SUBSTITUTE SHEET
16. The method of Claim 14 wherein the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval.
17. The method of Claim 1 wherein the compound is topotecan.
18. The method of Claim 10 wherein the compound is topotecan.
19. Use of a compound of of the formula:
wherein: a) X is hydroxy and R is trimethylammoniummethy1; b) X is hydroxy and R is N- methylpiperazinylmethyl; c) X is hydroxy and R is N-methylanilinomethyl; d) X is hydroxy and R is cyclohexylaminomethyl; e) X is hydroxy and R is N,N- dimethylaminoethyloxymethy1; f) X is hydroxy and R is cyclopropylamino ethy1; g) X is hydroxy and R is morpholinomethyl; h) X is hydroxy and R is aminomethyl; i) X is hydroxy and R is cyanomethyl; or j) X is hydroxy and R is dimethylaminomethyl or any pharmaceutically acceptable salts, hydrates and solvates thereof, in the manufacture of a medicament for use in the treatment of esophageal cancer.
20. The use of Claim 19 wherein the medicament is adapted for oral administration.
21. The use of Claim 19 wherein the medicament is adapted for parenteral administration.
SUBSTITUTESHEET
22. The use of Claim 19 wherein the compound is topotecan.
23. The use of Claim 20 wherein the compound is topotecan.
24. The use of Claim 21 wherein the compound is topotecan.
25. A pharmaceutical composition for use in the treatment of esophageal cancer in a human afflicted therewith comprising a compound of of the formula:
wherein: a) X is hydroxy and R is trimethylarrtmoniummethy1; b) X is hydroxy and R is N- methylpiperazinyImethy1; c) X is hydroxy and R is N-methylanilinomethyl; d) X is hydroxy and R is cyclohexylaminomethyl; e) X is hydroxy and R is N,N- dimethylaminoethyloxymethyl; f) X is hydroxy and R is cyclopropylaminomethyl; g) X is hydroxy and R is morpholinomethyl; h) X is hydroxy and R is aminomethyl; i) X is hydroxy and R is cyanomethyl; or j) X is hydroxy and R is dimethylaminomethyl or any pharmaceutically acceptable salts, hydrates and solvates thereof.
26. The composition of Claim 25 which is adapted for oral administration.
27. The composition of Claim 25 which is adapted for parenteral administration.
28. The composition of Claim 25 wherein the compound is topotecan.
29. The composition of Claim 26 wherein the compound is topotecan.
30. The composition of Claim 27 wherein the compound is topotecan.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65893691A | 1991-02-21 | 1991-02-21 | |
| US658936 | 1991-02-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0572563A1 true EP0572563A1 (en) | 1993-12-08 |
| EP0572563A4 EP0572563A4 (en) | 1993-12-29 |
Family
ID=24643326
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19920908199 Withdrawn EP0572563A4 (en) | 1991-02-21 | 1992-02-07 | Treatment of esophageal cancer |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0572563A4 (en) |
| JP (1) | JPH06505487A (en) |
| KR (1) | KR930702985A (en) |
| AU (1) | AU664172B2 (en) |
| CA (1) | CA2104449A1 (en) |
| MX (1) | MX9200725A (en) |
| PT (1) | PT100154A (en) |
| WO (1) | WO1992014470A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6395541B1 (en) | 1996-05-23 | 2002-05-28 | The Rockefeller University | Methods for the identification of compounds capable of inhibiting HIV-1 viral replication employing murine cell lines expressing human topoisomerase I |
| US6767704B2 (en) | 2000-03-27 | 2004-07-27 | Thomas Jefferson University | Methods of screening and diagnosing esophageal cancer by determining guanylin cyclase C expression |
| WO2001066144A2 (en) * | 2000-03-08 | 2001-09-13 | Rhode Island Hospital, A Lifespan Partner | Antineoplastic combination comprising an inhibitor of angiogenesis and an inhibitor of dna topoisomerase i enzyme activity |
| WO2007013671A2 (en) | 2005-07-27 | 2007-02-01 | Oncotherapy Science, Inc. | Method of diagnosing esophageal cancer |
| ES2371171B1 (en) * | 2010-06-08 | 2012-11-16 | Consejo Superior De Investigaciones Científicas (Csic) | CAMPTOTECHINE DERIVATIVES AS ANTITUMOR AGENTS. |
| CN102659800B (en) * | 2012-05-11 | 2014-09-03 | 中国药科大学 | Hypoxia-activated antitumor compounds and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0321122A2 (en) * | 1987-12-01 | 1989-06-21 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
-
1992
- 1992-02-07 JP JP4507807A patent/JPH06505487A/en active Pending
- 1992-02-07 WO PCT/US1992/001029 patent/WO1992014470A1/en not_active Application Discontinuation
- 1992-02-07 KR KR1019930702492A patent/KR930702985A/en not_active Application Discontinuation
- 1992-02-07 EP EP19920908199 patent/EP0572563A4/en not_active Withdrawn
- 1992-02-07 CA CA002104449A patent/CA2104449A1/en not_active Abandoned
- 1992-02-07 AU AU15406/92A patent/AU664172B2/en not_active Ceased
- 1992-02-21 MX MX9200725A patent/MX9200725A/en unknown
- 1992-02-21 PT PT100154A patent/PT100154A/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0321122A2 (en) * | 1987-12-01 | 1989-06-21 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
Non-Patent Citations (4)
| Title |
|---|
| CANCER CHEMOTHER REP. vol. 56, no. 1 , 1972 pages 95 - 101 C.G. MOERTEL ET AL 'Phase II study of camptothecin (NSC 100880) in the treatment of advanced gastrointestinal cancer.' * |
| PROC. AM. ASSOC. CANCER RES. ANNU. MEET. vol. 31 , 1990 page 436 M.R. MATTERN ET AL 'Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor SKF 104864.' * |
| PROC. ANNU. MEET. AM. SOC. CLIN. ONCOL. vol. 10 , 1991 page 117 Y. OHE ET AL 'Pharmacokinetics with a 5-day continuous infusion of a camptothecin derivative, CPT-11.' * |
| See also references of WO9214470A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| PT100154A (en) | 1993-05-31 |
| MX9200725A (en) | 1992-09-01 |
| AU1540692A (en) | 1992-09-15 |
| WO1992014470A1 (en) | 1992-09-03 |
| JPH06505487A (en) | 1994-06-23 |
| KR930702985A (en) | 1993-11-29 |
| AU664172B2 (en) | 1995-11-09 |
| EP0572563A4 (en) | 1993-12-29 |
| CA2104449A1 (en) | 1992-08-22 |
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