WO1990012321A1 - Radiosensibilisateurs avec ligand d'adn halogene pour la therapie anticancereuse - Google Patents

Radiosensibilisateurs avec ligand d'adn halogene pour la therapie anticancereuse Download PDF

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Publication number
WO1990012321A1
WO1990012321A1 PCT/AU1990/000122 AU9000122W WO9012321A1 WO 1990012321 A1 WO1990012321 A1 WO 1990012321A1 AU 9000122 W AU9000122 W AU 9000122W WO 9012321 A1 WO9012321 A1 WO 9012321A1
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WIPO (PCT)
Prior art keywords
halogenated
dna
ligand
hydroxy
halogen
Prior art date
Application number
PCT/AU1990/000122
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English (en)
Inventor
Roger Francis Martin
David Patterson Kelly
Original Assignee
The Cancer Institute Board
The University Of Melbourne
Anti-Cancer Council Of Victoria
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 The Cancer Institute Board, The University Of Melbourne, Anti-Cancer Council Of Victoria filed Critical The Cancer Institute Board
Publication of WO1990012321A1 publication Critical patent/WO1990012321A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy

Definitions

  • HALOGENATED DNA LIGAND RADIOSENSITISERS FOR CANCER THERAPY This invention relates to the use in cancer therapy of halogenated DNA ligands which induce radiation damage in DNA in response to ionising or ultraviolet radiation. More particularly, the invention is concerned with the use of such ligands as radiosensitisers.
  • Radiosensitisers are substances which when present during irradiation, enhance the cytotoxic effects of radiation.
  • the hypoxic radiosensitiser Misonidazole enhances the cytotoxic effect of X- and ⁇ - radiation.
  • the interaction between radiation and radiosensitiser is complex and difficult to predict.
  • both the radiosensitiser and the radiation are cytotoxic per se. their use in therapy is limited.
  • Photosensitisers are substances which when present, enhance the cytotoxic effects of ultraviolet or visible radiation.
  • photosensitisers are included in the term
  • ionising radiation is used herein to include photons having enough energy to ionise a bond, such as, a, ⁇ , and ⁇ rays from radioactive nuclei and x-rays.
  • Incorporation of a bromine or iodine atom into DNA using BUdR or IUdR is known to sensitise DNA to breakage by ionising or ultraviolet radiation.
  • the sensitisation is mediated by the uracilyl free radical formed by dissociation of the carbon-halogen bond in the BUdR or IUdR by UV and the same free radical is formed by a reaction of hydrated electrons produced by ionising radiation. It has been proposed that the uracilyl free radical initiates strand cleavage by abstraction of the hydrogen atom from the 2'-deoxyribose carbon on the adjacent nucleotide.
  • iodinated DNA ligand is a potent sensitiser of cell-kill by near UV.
  • irradiation with ionising or ultraviolet radiation generates free radicals very close to, but not actually on, the DNA.
  • DNA breaks are produced following abstraction of hydrogen atoms from DNA near the binding sites of the halogenated ligand.
  • halogenated DNA ligands may also act as sensitisers of ionising radiation.
  • Ultraviolet radiation is more effective at producing free radicals than ionising radiation.
  • ultraviolet radiation has a low tissue penetration and could only be used in the treatment of superficial tumours or in the specific killing of isolated tumour cells for example, in samples of bone marrow prior to bone marrow transplantation.
  • a radiosensitiser for use in cancer therapy which comprises a halogenated DNA ligand.
  • a method for enhancing the radiosensitiser for use in cancer therapy which comprises a halogenated DNA ligand.
  • a method for inducing radiation damage in DNA which comprises causing or allowing a halogenated DNA ligand to bind to DNA and irradiating the DNA and said bound ligand or the locus thereof with ionising or ultraviolet radiation.
  • the DNA ligand may be of any suitable known type e.g. an intercalating ligand such as an aminoacridine or a minor groove binding ligand such as bis-benzimidazole and those described in Baguley, V.C., (1982) J. Mol.
  • the ligand (with its attached halogen atom) is of a type which allows enhanced uptake, by endocytosis or other means, of the radiosensitiser into cells.
  • the minor groove binding ligand is a halogenated bis-benzimidazole of the general formula:
  • R 1 , R 2 , R 3 , R 4 and R 5 which may be the same or different, are selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitro or any other suitable non-deleterious substituent; and
  • R 6 is alkyl; phenyl; phenyl optionally substituted with halogen, hydroxy, alkoxy, nitro or any other
  • R 1 , R 2 , R 3 , R 4 and R 5 which are either the same or different, are selected from hydrogen, hydroxy, alkoxy, iodo and bromo;
  • R 6 is methyl, phenyl or phenylalkyl.
  • the halogenated ligand is preferably selected so as to bind at a location near the sugar chain of DNA so that the halogen free radical is sufficiently close to the potential target area in the sugar chain.
  • Figure 1 shows the 1.7% agarose gel of UV-B
  • FIG. 1 shows the DNA-sequencing gels of
  • Figure 3 shows the pBR322 restriction fragment used in the experiments involving higher resolution ( 16% acrylamide) sequencing gels
  • Figure 4 shows the relationship between UV-A dose and cell survival when iodoHoescht is added to the cell medium to a concentration of 4 ⁇ M; and Figure 5 shows the analysis of a large number of binding sites of DNA substrates derived from M13 clones of human alpha-DNA.
  • the UV spectrum of Hoechst 33258 has an absorption maximum at 338nm which shifts to 356nm upon binding to DNA. Substitution of iodine with the phenyl ring of the bis-benzimidazole shifts the maximum to 345nm.
  • UV-A (320-400nm) was used in preference to UV-B which closely coincides with the absorption of the halogenated nucleotides.
  • Maxam-Gilbert sequencing tracks regardless of whether or not the photolysis samples are treated with hot
  • Example 1 - ( Figure 1) Mixtures containing pBR322 DNA (l ⁇ g) and various amounts of HPLC-purified iodoHoechst 33258, in 20 ⁇ l of
  • Example 2 EcoR1-cut pBR322 DNA was 5'- 32 P-end labelled, cut with BamH1 and the 375 bp labelled fragment isolated by preparative polyacrylamide gel electrophoresis. Samples of the labelled fragment were mixed with carrier DNA and iodoHoechst 33258 and photolysed as described in Example 1. The final concentrations of iodoHoechst were l ⁇ M (lane 1), 2.5 ⁇ M (lane 4), and 5 ⁇ M (lanes 2 & 5), 10 ⁇ M
  • End-labelled restriction fragments were derived from pBR322.
  • the 375 bp fragments were prepared by 3'- or 5'- 32 P end labelling at the EcoR1 site, followed by subsequent cleavage with BamHl and then isolation by preparative polyacrylamide gel electrophoresis.
  • the dose-rate delivered to the monolayer was calculated to be approximately 50 ⁇ W cm -2 .
  • the flasks were covered with black adhesive vinyl, washed twice with ice cold
  • Example 5 - ( Figure 5) Clone alpha 32, which contains a 340 bp insert of human alpha RI-DNA in M13 mp9, was effectively 5'-end labelled as described below and UV irradiated in the presence of iodoHoechst 33258 as described in Example 1. Autoradiographs of DNA sequencing gels were analysed by laser densitometry and damage sites were quantified as very strong (VS), strong (S) or medium (M).
  • VS very strong
  • S strong
  • M medium
  • the iodoHoechst 33258 binding site is in capital letters.
  • the procedure for effectively 5'-end labelling M13 clone alpha 32 briefly involves pulse labelling the DNA immediately after the 17 bp sequencing primer with

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Saccharide Compounds (AREA)

Abstract

Le radiosensibilisateur décrit, qui est conçu pour être utilisé en radiothérapie, comprend un ligand d'ADN halogéné. On améliore la sensibilité de l'ADN à l'attaque par rayonnement en amenant ou en permettant la liaison du ligand d'ADN halogéné avec l'ADN, avant de soumettre l'ADN ou son site à un rayonnement ionisant ou ultra-violet. On provoque également une attaque par rayonnement de l'ADN en amenant ou en permettant la liaison du ligand d'ADN halogéné avec l'ADN et en exposant l'ADN et le ligand lié ou son site à un rayonnement ionisé ou ultra-violet.
PCT/AU1990/000122 1989-03-31 1990-03-30 Radiosensibilisateurs avec ligand d'adn halogene pour la therapie anticancereuse WO1990012321A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPJ346889 1989-03-31
AUPJ3468 1989-03-31

Publications (1)

Publication Number Publication Date
WO1990012321A1 true WO1990012321A1 (fr) 1990-10-18

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006831A1 (fr) * 1994-08-26 1996-03-07 Auckland Division Cancer Society Of New Zealand Inc. Nouveaux agents d'alkilation cibles sur l'adn
WO1997004776A1 (fr) * 1995-07-28 1997-02-13 The Inner And Eastern Health Care Network Radioprotecteurs
CN1302777C (zh) * 2002-04-02 2007-03-07 内尔维阿诺医学科学有限公司 包括取代的丙烯酰偏端霉素衍生物和放射治疗的抗肿瘤联合疗法
US10118920B2 (en) 2015-04-20 2018-11-06 Cellcentric Ltd Isoxazolyl substituted benzimidazoles
US10428065B2 (en) 2015-04-20 2019-10-01 Cellcentric Ltd Isoxazolyl substituted imidazopyridines

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988007986A2 (fr) * 1987-04-17 1988-10-20 Ire-Celltarg S.A. Composes utiles notamment pour la radiotherapie ou l'imagerie du cancer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988007986A2 (fr) * 1987-04-17 1988-10-20 Ire-Celltarg S.A. Composes utiles notamment pour la radiotherapie ou l'imagerie du cancer

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 106, No. 11, issued 16 March 1987 (Columbus, Ohio, USA); ZEDDA et al.: "Variation of the binding constants in gamma-irridiated DNA-9-aminoacridine complexes", see page 274, column 2, the abstract no. 80890k, APPL. PHYS. COMMUN 1986, 6(2-3), 131-41 (Eng). *
CHEMICAL ABSTRACTS, Volume 111, No. 3, issued 17 July 1989 (Columbus, Ohio, USA); KASSIS, AMIN I. et al.: "Radiotoxicity of an iodine-125-labeled DNA intercalator in mammalian cells", see page 308, column 2, the abstract no. 20195x, RADIAT. RES., 1989, 118(2), 283-94 (Eng). *
CHEMICAL ABSTRACTS, Volume 96, No. 1, issued 4 January 1982 (Columbus, Ohio, USA); KRUGLYAKOVA, K.E. et al.: "Investigation of the interaction of 9-aminoacridine with DNA damaged by UV light of different wavelength", see page 271, column 1, the abstract no. 2973a, STUD. BIOPHYS. 1981, 85(1), 57-8 (Russ). *
INTERNATIONAL JOURNAL OF RADIATION AND RELATED STUDIES IN PHYSICS, CHEMISTRY, AND MEDICINE, Volume 46, No. 4, 1984, p. 331-344, SMITH and ANDERSON: "Modification of the radiation sensitivity of human tumour cells by a bis-benzimidazole derivative". See pages 337-341 and 344. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006831A1 (fr) * 1994-08-26 1996-03-07 Auckland Division Cancer Society Of New Zealand Inc. Nouveaux agents d'alkilation cibles sur l'adn
US5968933A (en) * 1994-08-26 1999-10-19 Auckland Division Cancer Society Of New Zealand Inc. DNA-targeted alkylating agents
WO1997004776A1 (fr) * 1995-07-28 1997-02-13 The Inner And Eastern Health Care Network Radioprotecteurs
US6194414B1 (en) 1995-07-28 2001-02-27 The Inner And Eastern Health Care Network Radioprotectors
US6548505B1 (en) 1995-07-28 2003-04-15 Peter Maccallum Cancer Institute Radioprotectors
CN1302777C (zh) * 2002-04-02 2007-03-07 内尔维阿诺医学科学有限公司 包括取代的丙烯酰偏端霉素衍生物和放射治疗的抗肿瘤联合疗法
US10118920B2 (en) 2015-04-20 2018-11-06 Cellcentric Ltd Isoxazolyl substituted benzimidazoles
US10428065B2 (en) 2015-04-20 2019-10-01 Cellcentric Ltd Isoxazolyl substituted imidazopyridines

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