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WO1994004159A2 - Traitement du cancer a l'azt ou a l'aide d'agents d'alkylation ou de chelation - Google Patents

Traitement du cancer a l'azt ou a l'aide d'agents d'alkylation ou de chelation Download PDF

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Publication number
WO1994004159A2
WO1994004159A2 PCT/GB1993/001789 GB9301789W WO9404159A2 WO 1994004159 A2 WO1994004159 A2 WO 1994004159A2 GB 9301789 W GB9301789 W GB 9301789W WO 9404159 A2 WO9404159 A2 WO 9404159A2
Authority
WO
WIPO (PCT)
Prior art keywords
azt
mammal
pharmaceutically acceptable
agent
ester
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.)
Ceased
Application number
PCT/GB1993/001789
Other languages
English (en)
Other versions
WO1994004159A3 (fr
Inventor
Bangaru Chandrasekaran
David Stanley Duch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wellcome Foundation Ltd
Original Assignee
Wellcome Foundation Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Wellcome Foundation Ltd filed Critical Wellcome Foundation Ltd
Priority to AU49679/93A priority Critical patent/AU4967993A/en
Priority to EP93919464A priority patent/EP0655918A1/fr
Priority to JP6506072A priority patent/JPH08500356A/ja
Publication of WO1994004159A2 publication Critical patent/WO1994004159A2/fr
Publication of WO1994004159A3 publication Critical patent/WO1994004159A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the field of cancer therapy and particularly to chemotherapeutic methods of treating cancer as well as to pharmaceutical compositions for use in such methods.
  • Chemotherapy is an important method of treating cancer which comprises the administration of substances, which are usually to a greater or lesser degree cytotoxic, to a patient. Because of the nature of these compounds patients often suffer from side effects which can in many cases be quite severe.
  • Drugs 39(4) (1990) p 489 is a review of certain well known categories of anti-cancer agents.
  • 3'-azido-3'-deoxythymidine also known as A T or zidovudine
  • a T or zidovudine has been found to have a particularly beneficial clinical effect against a wide range of conditions associated with HTV infections such as Acquired Immune Deficiency Syndrome (AIDS), ALDS- related complex (ARC) and asymptomatic infections.
  • AIDS Acquired Immune Deficiency Syndrome
  • ALDS- related complex ARC
  • asymptomatic infections a particularly beneficial clinical effect against a wide range of conditions associated with HTV infections
  • This compound at low doses is generally very well tolerated by patients and is now widely used in the treatment of HTV infections.
  • AZT has been found to be useful in combination with certain known anti-cancer agents in the treatment of cancer.
  • US patent No. 5116823 discloses the use of AZT in combination with 5-fluorouracil (5-FU), its precursor 5-fluoro-2'-deoxyuridine (FTJDR) or methotrexate in the treatment of carcinomas, particularly of the colon.
  • the invention provides a method of treating cancer in a mammal such as a human which comprises administering to said mammal a potentiating effective amount of AZT, or a pharmaceutically acceptable salt or ester thereof, and an effective amount of an alkylating agent.
  • alkylating agents are chloromethine, cyclophosphamide, ifosfamide, melphalan and chlorambucil, with melphalan being preferred.
  • the two agents should be administered separately, such separate administration being carried out within a time period sufficient to allow the desired therapeutic effect to take place.
  • the administration of the AZT precedes administration of the alkylating agent.
  • AZT is administered both before and after administration of the alkylating agent.
  • AZT AZT
  • a pharmaceutically acceptable salt or ester thereof potentiates the effect of DNA intercalating agents producing synergistic cytotoxic effects in cancer cells.
  • a further embodiment of the invention provides a method of treating cancer in a mammal such as a human which comprises administering to said mammal a potentiating effective amount of AZT, or a pharmaceutically acceptable salt or ester thereof and an effective amount of a DNA intercalating agent.
  • intercalating agents are anthracyclines such as adriamycin or daunorubicin, with adriamycin being prefered.
  • the two agents should be administered separately, such separate administration being carried out within a time period sufficient to allow the desired therapeutic effect to take place.
  • the administration of the AZT precedes administration of the DNA interclating agent.
  • AZT is administered both before and after administration of the DNA intercalating agent.
  • the methods of the invention described above are particularly useful in treating breast, colon, ovarian, bladder and thyroid carcinomas, as well as both Hodgkin and non- Hodgkin lymphomas, lymphoblastic leukaemia and multiple myelomas.
  • the AZT, or a pharmaceutically acceptable salt or ester thereof, and the alkylating agent or DNA intercalating agent may be administered by any suitable route, including oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal and parenteral (including subcutaneous intramuscular, intravenous and intradermal). It will be appreciated that the preferred route or routes will vary with the condition and age of the recipient, the nature of the condition and other clinical factors.
  • a preferred route of administration would be via intravenous dosing, either by bolus or infusion.
  • the preferred daily dose range for AZT is l-25g/m2 as a constant i.v. infusion or 1- lOg/m ⁇ as a bolus dose.
  • the alkylating agent it is 5-50mg/m2, preferably 15- 25mg/m2, if given i.v. or 0.1-0.5mg/kg, preferably 0.25mg/kg if given orally.
  • the preferred dose range is 5-100mg/m2, preferably 20-
  • the doses of AZT and the alkylating or DNA intercalating agent can be administered as single doses or as a series of sub-doses administered at appropriate intervals.
  • AZT AZT
  • a pharmaceutically acceptable salt or ester thereof, and the other agent are employed in an appropriate ratio whereby the above-mentioned therapeutic effects are obtained.
  • the AZT and the alkylating or DNA intercalating agent used in the method of the invention can be presented in any conventional pharmaceutically effective form, e.g. pharmaceutical formulations comprising the active ingredient together with one or more pharmaceutically acceptable carriers or excipients.
  • AZT for use in the potentiation of the anticancer activity of an alkyiating agent or DNA intercalating agent
  • Suitable formulations include those adapted for oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredients with the other components. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then if necessary shaping the product.
  • Formulations of the present invention adapted for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredients, as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water- in-oil liquid emulsion.
  • the active ingredients may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as a powder or granules, optionally mixed with a binder (eg. povidone. gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (eg. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Formulations for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub- dose, as herein above recited, or an appropriate fraction thereof, of active ingredients.
  • the two active compounds can be presented together, for instance in a unitary pack or the like, together with suitable instructions regarding their administration. Therefore, in a further aspect the present invention provides a pack which consists essentially of AZT, or a pharmaceutically acceptable salt or ester thereof, and an alkylating agent, provided separately therein and presented for co-administration to a patient. Similarly the invention also provides a pack which consists essentially of AZT, or a pharmaceutically acceptable salt or ester thereof, and a DNA intercalating agent, provided separately therein and presented for co-administration to a patient.
  • Such packs can be presented as single dose or multi-dose depending on the treatment regime and other clinical factors.
  • Example 1 The following examples serve only to illustrate the present invention: Example 1
  • IC50 value for AZT, melphalan, navelbine, ara-C, 5-FU and methotrexate were determined as 40, 1, 0.05, 0.4, 3 and 0.004 ⁇ M respectively against HCT-8 cells and 100, 3, 0.0015, 0.03, 1 and 0.002 ⁇ M respectively against WiDr cells.
  • the IC50 value for adriamycin was O.OOl ⁇ M against WiDr cells.
  • Figure 1 shows an isobologram analysis of WiDr cells exposed to AZT and melphalan. This shows synergy which is both time and schedule dependent. Data points on the dotted line in the isobologram indicate an additive effect for the drug combination. Data points below this line represent synergy and above the line represent antagonism.
  • Table 1 shows the interaction of AZT with anti-cancer agents defined in terms of additive, synergistic, or antagonistic effects.
  • Figures 4 and 5 show the number of days in each case for two tumour doublings to occur. In both tumours AZT significantly potentiated the activity of melphalan.
  • formulations A, B and C were prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
  • formulations, D and E were prepared by direct copmpression of the admixed ingredients.
  • the lactose used in formulation E was of the direct compression type (Dairy Crest - "Zeparox")
  • the formulation was prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression. mg/tablet
  • Drug release takes place over a period of about 6-8 hours and was complete after 12 hours.
  • a capsule formulation was prepared by admixing the ingredients of Formulation D in Example 2 above and filling into a two-pan hard gelatin capsule.
  • Formulation B (infra) was prepared in a similar manner.
  • Capsules were prepared by melting the Macrogel 4000 B.P., dispersing the AZT in the melt and filling the melt into a two-part hard gelatin capsule.
  • Capsules were prepared by dispersing the AZT in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin.
  • the following controlled release capsule formulation was prepared by extruding ingredients a, b and c using an extruder, followed by spheronisation of the extrudate and drying.
  • the dried pellets were than coated with release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule.
  • the AZT was dissolved in most of the water (35°-40°C) and the pH adjusted to between 4.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate - the batch was then made up to volume with the water and filtered through a sterile micropore filter into a sterile 10ml amber glass vial (type 1) and sealed with sterile closures and overseals.
  • Formulation B
  • the AZT was dissolved in the glycoflirol.
  • the benzyl alcohol was then added and dissolved, and water added to 3 ml.
  • the mixture was then filtered through a sterile micropore filter and sealed in 3ml amber glass vials (type 1).
  • the AZT was used as a powder wherein at least 90% of the particles were of 631m diameter or less.
  • Witepsol HI 5 was melted in a steam-jacketed pan at 45 C maximum.
  • the AZT was sifted through a 2001m sieve and added to the molten base with mixing, using a silverson fitted with a cutting head, until a smooth dispersion was achieved. o Maintaining the mixture at 45 C, the remaining Witepsol HI 5 was added to the suspension and stirred to ensure homogenous mix. The entire suspension was passed through a 2501m stainless steel screen and, with continuous stirring, was allowed to o o o cool to 40 C. At a temperature of 38 C to 40 C 2.02g of the mixture was filled into suitable plastic moulds. The suppositories were allowed to cool to room temperature.
  • Stopper with sterile closures and secure with alLiminium collars.
  • the freeze-dried melphalan hydrochloride is prepared as described in Example 1.
  • the solvent-diluent is prepared as described in (a) above.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des procédés de traitement du cancer chez un mammifère qui consistent à administrer audit mammifère une dose efficace de potentialisation d'AZT, un sel ou un ester pharmaceutiquement acceptable de cette dernière, combinée à une dose efficace d'un agent d'alkylation ou un agent intercalant d'ADN. L'agent d'alkylation préféré est le melphalan et l'agent intercalant d'ADN l'adriamycine.
PCT/GB1993/001789 1992-08-24 1993-08-23 Traitement du cancer a l'azt ou a l'aide d'agents d'alkylation ou de chelation Ceased WO1994004159A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU49679/93A AU4967993A (en) 1992-08-24 1993-08-23 Treatment of cancer with azt and alkylating or intercalating agents
EP93919464A EP0655918A1 (fr) 1992-08-24 1993-08-23 Traitement du cancer a l'azt ou a l'aide d'agents d'alkylation ou de chelation
JP6506072A JPH08500356A (ja) 1992-08-24 1993-08-23 Ａｚｔおよびアルキル化剤または挿入剤による癌の処置

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9217998.5 1992-08-24
GB929217998A GB9217998D0 (en) 1992-08-24 1992-08-24 Methods of treating cancer

Publications (2)

Publication Number Publication Date
WO1994004159A2 true WO1994004159A2 (fr) 1994-03-03
WO1994004159A3 WO1994004159A3 (fr) 1994-04-14

Family

ID=10720879

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/001789 Ceased WO1994004159A2 (fr) 1992-08-24 1993-08-23 Traitement du cancer a l'azt ou a l'aide d'agents d'alkylation ou de chelation

Country Status (8)

Country Link
EP (1) EP0655918A1 (fr)
JP (1) JPH08500356A (fr)
AU (1) AU4967993A (fr)
GB (1) GB9217998D0 (fr)
IL (1) IL106763A0 (fr)
MX (1) MX9305106A (fr)
WO (1) WO1994004159A2 (fr)
ZA (1) ZA936166B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6338843B1 (en) * 1997-06-12 2002-01-15 Ml Laboratories Biologically active materials
WO2008082602A3 (fr) * 2006-12-28 2008-08-28 Idenix Pharmaceuticals Inc Composes et compositions pharmaceutiques destines au traitement des troubles hepatiques
US20130209550A1 (en) * 2010-07-28 2013-08-15 Life Technologies Corporation Anti-Viral Azide Containing Compounds
US20180110780A1 (en) * 2015-04-30 2018-04-26 Taiho Pharmaceutical Co., Ltd. Agent for alleviating side effect of antitumor drug

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018136920A1 (fr) * 2017-01-23 2018-07-26 Health Research, Inc. Inhibition de transcriptase inverse endogène et ciblage de cellules pour une prophylaxie et une thérapie anti-cancéreuse et anti-vieillissement

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3821676A1 (de) * 1988-06-28 1990-02-08 Werner E G Prof Dr Mueller Verwendung von avaron oder avaron-derivaten in kombination mit 3'-azido-3'-deoxythymidin zur antiviralen therapie
US5116823A (en) * 1990-02-27 1992-05-26 Roger Williams General Hospital Drug combinations containing AZT

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6338843B1 (en) * 1997-06-12 2002-01-15 Ml Laboratories Biologically active materials
WO2008082602A3 (fr) * 2006-12-28 2008-08-28 Idenix Pharmaceuticals Inc Composes et compositions pharmaceutiques destines au traitement des troubles hepatiques
US20130209550A1 (en) * 2010-07-28 2013-08-15 Life Technologies Corporation Anti-Viral Azide Containing Compounds
US20180110780A1 (en) * 2015-04-30 2018-04-26 Taiho Pharmaceutical Co., Ltd. Agent for alleviating side effect of antitumor drug

Also Published As

Publication number Publication date
WO1994004159A3 (fr) 1994-04-14
JPH08500356A (ja) 1996-01-16
MX9305106A (es) 1994-03-31
AU4967993A (en) 1994-03-15
ZA936166B (en) 1995-02-23
IL106763A0 (en) 1993-12-08
GB9217998D0 (en) 1992-10-07
EP0655918A1 (fr) 1995-06-07

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