JPH08500356A - Treatment of cancer with AZT and alkylating or intercalating agents - Google Patents

Abstract

  (57) [Summary] The present invention relates to a method for treating cancer in a mammal, which comprises administering an enhancing effective amount of AZT, or a pharmaceutically acceptable salt or ester thereof together with an effective amount of an alkylating agent or a DNA intercalating agent. It consists of The preferred alkylating agent is melphalan, while the preferred DNA intercalating agent is adriamycin.

Description

DETAILED DESCRIPTION OF THE INVENTION Treatment of Cancer with AZT and Alkylating or Intercalating Agents The present invention relates to the field of cancer therapy, in particular to cancer chemotherapy and pharmaceutical compositions for use in this method. Chemotherapy is an important method of treating cancer, which usually consists of administering to the patient a substance that is more or less cytotoxic. Due to the nature of these compounds, patients often suffer from side effects, which in some cases can be severe. Drugs 39 (4) (1990), p. 489, provides an overview of certain well-known categories of anticancer agents. 3'-azido-3'-deoxythymidine [this compound, also known as AZT or zidovudine], is associated with acquired immunodeficiency syndrome (AIDS), AIDS-related complications (ARC) and no It has been found to have a particularly beneficial clinical effect on a wide range of conditions associated with HIV infection, such as symptomatic infections. At low doses, this compound is generally well tolerated by patients and is currently widely used in the treatment of HIV infection. However, in addition to this, AZT has also been found to be useful in the treatment of cancer in combination with certain known anti-cancer agents. US Patent No. 5116823 uses AZT in combination with 5-fluorouracil (5-FU), its precursor 5-fluoro-2'-deoxyuridine (FUDR) or methotrexate for the treatment of carcinomas, especially colon cancer. It is described to do. It has been found by the present invention that the action of alkylating agents or DNA intercalating agents (intercalating agents) as anti-cancer agents is enhanced by using AZT in combination with them. This enhancement results in a surprisingly large synergistic cytotoxic effect. Therefore, treatment with this combination is more effective than treatment with either of the above compounds. Accordingly, in a first aspect, the invention provides a method of treating cancer in a mammal, such as a human, wherein the method comprises an enhancing effective amount of AZT, or a pharmaceutically acceptable salt or ester thereof and an effective amount of alkyl. The agent comprises administering to the mammal. Examples of such alkylating agents include chloromethine, cyclophosphamide, ifosfamide, melphalan and chlorambucil, with melphalan being preferred. Preferably, the two drugs should be administered separately, with the separate administrations occurring within a time sufficient to produce the desired therapeutic effect. More preferably, AZT is administered prior to administration of the alkylating agent. Most preferably, AZT is administered both before and after administration of the alkylating agent. Furthermore, the present inventor has found that administration of AZT or a pharmaceutically acceptable salt or ester thereof enhances the action of the DNA intercalating agent and causes a synergistic cytotoxic action in cancer cells. Accordingly, in another aspect, the invention provides a method of treating cancer in a mammal, such as a human, which method comprises enhancing an effective amount of AZT, or a pharmaceutically acceptable salt or ester thereof, and an effective amount of a DNA insert. Administering the agent to the mammal. Examples of such intercalating agents include adriamycin or daunorubicin, with adriamycin being preferred. Preferably, the two drugs should be administered separately, with the separate administrations occurring within a time sufficient to produce the desired therapeutic effect. More preferably, the administration of AZT is performed prior to the administration of the DNA intercalating agent. Most preferably, AZT is administered both before and after administration of the DNA intercalating agent. The methods of the invention described above are particularly useful for treating breast cancer, colon cancer, ovarian cancer, bladder cancer and thyroid cancer, as well as Hodgkin and non-Hodgkin's lymphoma, lymphocytic leukemia and multiple myeloma. In the above method, AZT or a pharmaceutically acceptable salt or ester thereof and an alkylating agent or DNΛ insertion agent is orally, rectally, nasally, topically (including transdermal, buccal and sublingual), vaginal and parenteral ( Administration (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route or routes will depend on the condition and age of the recipient, the type of condition, and other clinical factors. However, the preferred route of administration is the intravenous route, either by bolus or infusion. The preferred daily dose range for AZT is a constant i. v. 1-25 g / m ² as an infusion or 1-10 mg / m ² as a bolus dose. In the case of an alkylating agent, i. v. When administered, it is 5-50 mg / m ² , preferably 15-25 mg / m ² , and when administered orally, it is 0.1-0.5 mg / kg, preferably 0.25 mg / kg. . Suitable dosage range of DNA intercalating agent, 5- 100mg / m ^2, preferably 20-60 mg / m ^2. The doses of these AZTs and alkylating or DNA intercalating agents can be administered as single doses or as a series of divided doses administered at appropriate intervals. AZT or a pharmaceutically acceptable salt or ester thereof, and other therapeutic agents can be used in an appropriate ratio to obtain the above-mentioned therapeutic effect. The AZT and alkylating agent or DNA intercalating agent used in the method of the present invention may be in any conventional pharmaceutically effective form, for example the active ingredient in one or more pharmaceutically acceptable carriers or It can be provided as a pharmaceutical composition containing together with an auxiliary agent. Another aspect of the invention is: a) AZ T for use in enhancing the anti-cancer activity of an alkylating agent or DNA intercalating agent, and b) for enhancing the anti-cancer activity of an alkylating agent or DNA intercalating agent. The use of AZT for the preparation of a medicament according to. As mentioned above, the carrier, auxiliary or diluent must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the patient. Suitable compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. To do. These compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the other ingredients. In general, these compositions are prepared by uniformly and intimately admixing the active ingredient with liquid or finely divided solid carriers or both, and then, if necessary, shaping the product. Suitable for oral administration, the compositions of the present invention may be formulated as divided units such as capsules, sachets or tablets, each containing a predetermined amount of active ingredient, as a powder or granules, in an aqueous or non-aqueous liquid. As a solution or suspension, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a lozenge, electuary or paste. A tablet may be made by compression or molding with any one or more ingredients. Compressed tablets contain the active ingredients in free-flowing form such as powders or granules, optionally with binders (eg povidone, gelatin, hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrating agents (eg sodium starch). It can be prepared by mixing with glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant and compressing with a suitable machine. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. These tablets may, if desired, be coated or scored and may also be formulated so as to give a controlled release of the active ingredient employed therein, eg Hydroxypropyl methylcellulose can be used in various proportions to obtain the desired release profile. Compositions for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which are isotonic with antioxidants, buffers, bacteriostats and the blood of the intended recipient of the composition. A solute), and aqueous and non-aqueous sterile suspensions, which suspensions may contain suspending agents and thickening agents. These compositions may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and also just prior to use, requiring only the addition of a sterile liquid carrier, such as water for injection, freezing. It can also be stored in a dried (vacuum freeze-dried) state. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the above type. Suitable unit dosage forms are those containing an active ingredient, as described above, in daily doses or units, daily fractional doses, or an appropriate fraction thereof. The two active compounds may be presented together, for example in a single pack, with the appropriate instructions relating to their administration. Accordingly, in another aspect, the invention provides a pack wherein AZT or a pharmaceutically acceptable salt or ester thereof and an alkylating agent are provided separately therein and adapted for combined administration to a patient. I will provide a. Similarly, the invention also provides a pack in which the AZT or a pharmaceutically acceptable salt or ester thereof and the DNA intercalating agent are separately provided therein and adapted for combined administration to a patient. . Such packs may be provided in single or multiple dose forms depending on the treatment regimen or other clinical factors. The following examples have the sole purpose of illustrating the present invention: Example l In Vitro Enhancement of Antitumor Pharmaceutical Activity by AZT AZT and the Anticancer Agents Clinically Used, Melphalan, Navelbine The interaction between 5-fluorouracil (5-FU), methotrexate, cytosine arabinoside (ara-C) and adriamycin was tested in the human colon carcinoma cell lines HCT-8 and WiDr. These cells were grown in the presence of RPMI-1640 containing 10% fetal bovine serum and 10 nM Leucovorin and no folate. IC ₅₀ values for AZT, melphalan, navelbine, ara-C, 5-FU and methotrexate were 40, 1, 0.05, 0.4 3, 3 and 0.004 μM for HCT-8 cells, respectively. Yes, and against WiDr cells were determined to be 100, 3, 0.0015, 0.03, 1 and 0.002 μM, respectively. The IC ₅₀ values of adriamycin against WiDr cells was 0.001 .mu.M. FIG. 1 shows an isobologram analysis of WiDr cells exposed to AZT and melphalan. This figure shows a synergistic effect that is both time elapsed and plan dependent. The data points on the dotted line of this isobologram show the additive effects associated with the drug combination. Data points below this dotted line indicate synergy and data points above this dotted line indicate antagonism. Table 1 shows the interaction between AZT and specific anticancer agents in terms of additive effect, synergistic effect and antagonistic effect. A clonogenic analysis was also performed and showed a 6-fold maximum synergistic effect of melphalan on HCT-8 cells. As can be seen from Figures 2 and 3, this synergistic effect is also time-dependent and plan-dependent. Example 2 In Vivo Enhancement of Antitumor Pharmaceutical Activity by AZT In these studies, the effect of AZT to enhance melphalan activity in vivo on the A2780 human ovarian carcinoma cell line and the COLO320 human colon carcinoma cell line was evaluated. The tumor was subcutaneously transplanted into nude mice, and when the tumor reached 100-200 mg, antitumor treatment was started. Animals receiving AZT were dosed with AZT at a dose of 400 mg / kg three times at time points 0, 3 and 6 hours. Animals receiving melphalan were given melphalan at a single dose of 10 mg / kg, or Table 1, 15 mg / kg, at the indicated times. Figures 4 and 5 show the number of days in each case until the two tumors doubled. In both tumors, AZT significantly enhanced the effects of melphalan. Example 3 AZT Tablet Composition The following Formulations A, B and C were prepared by wet granulating these ingredients with a povidone solution, followed by the addition of magnesium stearate followed by compression. Formulation A Formulation B Formulation C Formulations D and F below were made by direct compression of these mixed components. The lactose used in formulation E was lactose in direct compression [Daily Crest "Zeparox" (Zeparox)]. Formulation D Formulation F Formulation F (Controlled Release Formulation) This formulation was prepared by wet granulating the ingredients (below) with a povidone solution followed by the addition of magnesium stearate followed by compression. Drug release occurred over approximately 6-8 hours and ended after 12 hours. Example 4 Capsule Formulation Formulation A The ingredients of Formulation D from Example 2 above were mixed and then filled into a two-part hard gelatin capsule. Formulation B (below) was prepared in a similar manner. Formulation B Formulation C This capsule is Macrogel 4000B. P. Was prepared by melting AZT in the melt and then filling the melt into a two-part hard gelatin capsule. Formulation D The capsules were prepared by dispersing AZT in lecithin and arachis oil and then filling the dispersion into soft elastic gelatin. Formulation E (Controlled Release Capsule) The following controlled release capsule formulation was prepared by extruding components a, b and c using an extruder, spheronizing the extruded product and then drying. This dried pellet was then coated with a controlled release membrane (d) and then filled into a two-part hard gelatin capsule. Example 5 Injectable formulation Formulation A AZT was dissolved in most of water (35 ° C-40 ° C), and the pH was adjusted with hydrochloric acid or sodium hydroxide as needed. The batch was then made up to volume with water and then filtered through a sterile micropore filter into a sterile amber glass ampoule (Type 1), sealed with a sterile stopper and then oversealed. Formulation B Example 6 intramuscular injection AZT was dissolved in glycofurol. Benzyl alcohol was then added and dissolved, then water was added to 3 ml. The mixture was filtered through a sterile micropore filter and sealed in a 3 ml amber glass vial (type 1). Example 7 Suppository 1/5 of Witepsol H15 was melted in a steam-jacketed pan at a maximum of 45 ° C. AZT was fractionated through a 200 lm sieve and then added to the above melt with mixing using a Silverson equipped with a cutting blade to give a smooth dispersion. The mixture was maintained at 45 ° C. and the remaining Witepsol H15 was added to the suspension and stirred to ensure uniform mixing. The entire suspension was passed through a 250 lm stainless steel screen and then allowed to cool to 40 ° C. with continuous stirring. At a temperature of 38 ° C-40 ° C, 2.02 g of this mixture was filled into a suitable plastic mold. The suppository was allowed to cool to room temperature. Example 8 Pessary Pessaries were made by directly mixing the above ingredients and then directly compressing the resulting mixture. Example 9 Melphalan i. v. Formulation (a) Composition (i) Method Prepare a suitable hydrochloric acid diluent in water for injection. Add melphalan to part of the water for injection. Add hydrochloric acid solution and stir to complete dissolution. Add povidone and dissolve. Make constant weight with water for injection. The solution is sterilized by sterile filtration. Fill into sterile vials. Lyophilize. The vial is stoppered and sealed. Composition (ii) Method Sodium citrate is dissolved in a portion of the water for injection. Add a mixture of propylene glycol and ethanol. Make constant volume with water for injection. The solution is sterilized by sterile filtration. Fill into sterile ampoules or vials. Close with a sterile stopper and secure with an aluminum collar. Upon addition of composition (ii) to composition (i), the lyophilized product is rapidly reconstituted to give an injectable solution in the pH range 6-7.5. (B) Composition (i) Method Lyophilized melphalan hydrochloride is prepared as described in Example 1. The composition (ii) solvent-diluent is prepared as described in (a) above.

[Procedure Amendment] Patent Act Article 184-8 [Submission date] August 25, 1994 [Correction content] The scope of the claims   1. A method for treating cancer in a mammal, which comprises enhancing effective amount of AZT, or a medicament thereof. Acceptable salt or ester and an effective amount of alkylating agent as described above. Consists of AZT or its pharmaceutically acceptable salt Prior to administration of the alkylating agent or the alkylating agent The method of treatment administered together with administration of.   2. AZT, or its pharmaceutically acceptable salt or ester for resolution The method of claim 1, wherein multiple doses are administered.   3. 2. An additional dose of AZT is administered after administration of the alkylating agent. Or the method of claim 2.   4. A method according to any one of claims 1-3, wherein the alkylating agent is melphalan. The method described.   5. AZT, or a pharmaceutically acceptable salt or ester thereof and (or Or) the alkylating agent is administered as a bolus or by injection. The method described.   6. A method for treating cancer in a mammal, which comprises enhancing effective amount of AZT, or a medicament thereof. Acceptable salt or ester and an effective amount of the DNA intercalating agent as described above. Consists of AZT or its pharmaceutically acceptable salt The method of treatment in which the ester or the ester is administered prior to the administration of the DNA intercalating agent.   7. After administration of the above DNA intercalating agent, a second dose of AZT was administered to the mammal. The method according to claim 6, which is provided.   8. The method according to claim 6 or 7, wherein the DNA intercalating agent is adriamycin. The method described.   9. 9. The method according to any one of claims 1-8, wherein the mammal is a human.   Ten. Basically, AZT or its pharmaceutically acceptable salt or ester And an alkylating agent, which is provided separately there , A cancer treatment pack that is present for combined administration to a mammal.   11. Basically, AZT or its pharmaceutically acceptable salt or ester And the DNA intercalating agent, which is separately prepared there. And a cancer treatment pack that is present for combined administration to a mammal.   12. The pack according to claim 10 or 11, wherein the mammal is a human. .   13. The pack according to claim 10, wherein the alkylating agent is melphalan.   14. AZ for use in enhancing anti-cancer activity of alkylating or DNA intercalating agents T   15． Preparation of medicine for enhancing anti-cancer activity of alkylating agent or DNA intercalating agent Use of AZT for.

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Claims (1)

[Claims]   1. A method for treating cancer in a mammal, which comprises enhancing effective amount of AZT, or a medicament thereof. Acceptable salt or ester and an effective amount of alkylating agent as described above. A method of treatment comprising administering to an animal.   2. AZT or its pharmaceutically acceptable salt or ester is The method of claim 1, wherein the method is administered prior to the administration of the rukylling agent.   3. AZT, or a pharmaceutically acceptable salt or ester thereof, 3. The method of claim 1 or claim 2, wherein the dose is administered multiple times.   4. The method of claim 3, wherein the additional dose of AZT is administered with an alkylating agent. Method.   5. 6. The additional dose of AZT is administered after the administration of the alkylating agent. 4. The method according to any one of 4.   6. The alkylating agent is melphalan, according to any one of claims 1-5. The method described.   7. AZT, or a pharmaceutically acceptable salt or ester thereof and (or Or) the alkylating agent is administered as a bolus or by injection. The method described.   8. A method for treating cancer in a mammal, which comprises enhancing effective amount of AZT, or a medicament thereof. Acceptable salt or ester and an effective amount of the DNA intercalating agent as described above. A method of treatment comprising administering to an animal.   9. AZT, or a pharmaceutically acceptable salt or ester thereof can be prepared as described above in D The method according to claim 8, which is administered prior to administration of the NA intercalating agent.   Ten. After administration of the above DNA intercalating agent, a second dose of AZT was administered to the mammal. The method of claim 9, wherein   11. 11. The DNA intercalating agent is adriamycin, according to any one of claims 8 to 10. The method described in one.   12. 12. The method according to any one of claims 1-11, wherein the mammal is a human. .   13. Basically, AZT or its pharmaceutically acceptable salt or ester And an alkylating agent, which is provided separately there , A cancer treatment pack that is present for combined administration to a mammal.   14. Basically, AZT or its pharmaceutically acceptable salt or ester And a DNA intercalating agent, which is separately prepared there , A cancer treatment pack that is present for combined administration to a mammal.   15． The pack according to claim 13 or 14, wherein the mammal is a human. .   16. 14. The pack of claim 13, wherein the alkylating agent is melphalan.   17． AZ for use in enhancing anti-cancer activity of alkylating or DNA intercalating agents T   18. Preparation of medicine for enhancing anti-cancer activity of alkylating agent or DNA intercalating agent Use of AZT for.