AU639920B2 - Halogenated dna ligand radiosensitisers for cancer therapy - Google Patents
Halogenated dna ligand radiosensitisers for cancer therapyInfo
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- AU639920B2 AU639920B2 AU54167/90A AU5416790A AU639920B2 AU 639920 B2 AU639920 B2 AU 639920B2 AU 54167/90 A AU54167/90 A AU 54167/90A AU 5416790 A AU5416790 A AU 5416790A AU 639920 B2 AU639920 B2 AU 639920B2
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Description
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. For example, the hypoxic radiosensitiser Misonidazole, enhances the cytotoxic effect of X- and γ- radiation. Although studied for many years, the
interaction between radiation and radiosensitiser is complex and difficult to predict. Moreover, as 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. For the purposes of this specification photosensitisers are included in the term
radiosensitisers.
The term ionising radiation is used herein to include photons having enough energy to ionise a bond, such as, a, β, and γ 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. We have investigated the induction of DNA strand breaks by UV-irradiation of DNA-bound iodoHoechst 33258 (4-[5"-(4'''-methylpiperazin-1'''-yl)-2",5'-bi-1H- benzimidazol-2'-yl]phenol), a sequence-selective DNA ligand that binds in the minor groove of DNA. Analysis of the fragmentation products on DNA sequencing gels
indicates that strand cleavage results from hydrogen atom abstraction at the 5'-deoxyribose-carbon, by analogy with cleavage by neocarcinostatin. It is believed that photolytic deiodination of the DNA ligand leaves a carbon-centred free radical adventitiously located in the minor groove, resulting in hydrogen atom abstraction and consequent strand cleavage. We have also found that the iodinated DNA ligand is a potent sensitiser of cell-kill by near UV. When the ligand is attached to the DNA, 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. Our results indicate that halogenated DNA ligands may also act as sensitisers of ionising radiation. Ultraviolet radiation is more effective at producing free radicals than ionising radiation. However, 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.
Thus, according to one aspect of the present
invention there is provided a radiosensitiser for use in cancer therapy which comprises a halogenated DNA ligand. According to another aspect of the present invention there is provided a method for enhancing the
susceptibility of DNA to radiation damage, which
comprises causing or allowing a halogenated DNA ligand to bind to the DNA before subjecting the DNA or the locus thereof to ionising or ultraviolet radiation.
According to a further aspect of the present invention there is provided 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.
Cell. Biochem. 43: 167-181, for example, compounds having the following structural formulae:
wherein X is halogen. Advantageously, 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. In a preferred embodiment the minor groove binding ligand is a halogenated bis-benzimidazole of the general formula:
wherein R1, R2, R3, R4 and R5, 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
R6 is alkyl; phenyl; phenyl optionally substituted with halogen, hydroxy, alkoxy, nitro or any other
suitable non-deleterious substituent; or phenylalkyl
optionally substituted with halogen, hydroxy, alkoxy, nitro or any other suitable non-deleterious substituent. Particularly preferred compounds of formula (I) are those wherein
R1, R2, R3, R4 and R5, which are either the same or different, are selected from hydrogen, hydroxy, alkoxy, iodo and bromo; and
R6 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.
The basis of the invention is further shown by reference to the accompanying drawings in which:-
Figure 1 shows the 1.7% agarose gel of UV-B
irradiated mixtures of plasmid DNA and iodoHoechst 33528;
Figure 2 shows the DNA-sequencing gels of
fractionated 5'-32P-end-labelled restriction fragment cleavage products;
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 4μM; and
Figure 5 shows the analysis of a large number of binding sites of DNA substrates derived from M13 clones of human alpha-DNA.
Details of the experimental methods are given in the Examples which follow.
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.
Therefore, UV-A (320-400nm) was used in preference to UV-B which closely coincides with the absorption of the halogenated nucleotides.
Irradiation of mixtures of plasmid DNA and
iodoHoechst 33258 clearly resulted in marked strand cleavage (Figure 1) which was detectable at. input ratios below one DNA ligand per 50 bp. No detectable cleavage was obtained by UV irradiation of DNA with the same dose of UV-A in the presence of unsubstituted Hoechst 33258 (not shown), nor with UV irradiation only. Similar results have been obtained with the
following compounds of formula (I) wherein
R1 = R4 = R5 = H, R2 = I, R3 = OH, R6 = CH3;
R1 = R5 = H, R2 = R4 = I, R3 = OH, R6 = CH3;
R1 = R4 = R5 = H, R2 = I, R3 = OCH3, R6 = CH3;
R1 = R5 = H, R2 = R4 = I, R3 = OCH3, R6 = CH3; and R1 = R3 = R4 = R5 = H, R2 = Br, R6 = CH3.
To analyse the strand breaks in more detail
5'- 32P-end-labelled restriction fragments were used and
the cleavage products were fractionated on DNA-sequencing gels. As illustrated in Figure 2, these experiments showed that the UV-induced cleavage was at discrete sites along the DNA and always just to the 3' side of a ligand binding site comprised of 3 or more consecutive AT base pairs. The extent of breakage generally increased with higher concentrations of the iodinated ligand but at 20μM (compared to 75 μM DNA bp) more generalised breakage was apparent. Experiments with DNA substrate derived from M13 clones of human alpha-DNA enabled the analysis of a large number of binding sites and for all the stronger cleavage sites, the cleavage occurred at the 3'-end of the indicated binding site. The results are set out in Figure 5.
A more detailed appreciation of the mechanism of photolytic cleavage came from experiments with higher resolution (16% acrylamide) sequencing gels, using a 100 bp pBR322 restriction fragment end-labelled 3' or 5', at either end of the fragment (Figure 3). With 5'-labelled target DNA, the site of cleavage is always 3' to the ligand binding site and the mobility of the cleavage products coincide with corresponding bands in the
Maxam-Gilbert sequencing tracks, regardless of whether or not the photolysis samples are treated with hot
piperidine. On the other hand, the situation was more complex for experiments with 3'-labelled target DNA fragments. The major 3'-labelled fragment species was always about 2 nucleotides longer than anticipated from the 5'-labelled data, and its mobility sometimes
different from the "nearest" Maxam-Gilbert band.
Alternatively, treatment of the photolysis samples with hot piperidine shortened the major species, bringing
the cleavage site to the same nucleotide as seen for the corresponding 5'-labelled experiment. Moreover, the mobility of the piperidine-treated 3'-labelled species was coincident with the Maxam-Gilbert band. This pattern of mobilities is exactly the same as that described for neocarcinostatin cleavage of DNA.
Extensive investigations have indicated that a free radical species in neocarcinostatin abstracts a hydrogen atom from the 5'-carbon of deoxyribose and that
subsequent oxidation at that carbon results in a strand break leaving the termini of a 5'-carbon aldehyde and 3'-phosphoryl. Subsequent piperidine treatment removes the base-sugar aldehyde leaving a 5'-phosphoryl group.
It is concluded by analogy that iodoHoeshst 33258 photolysis involves a similar cleavage mechanism,
initiated by photolysis of the carbon-iodine bond and formation of a carbon-centred free radical on the DNA ligand, which subsequently abstracts a hydrogen atom from the 5'-carbon.
Cytotoxicity studies have shown that iodoHoechst is also a potent sensitiser in situ. When the DNA ligand was added to the medium to a concentration of 4μM, irradiation resulted in 3-4-log cell kill at a UV-A dose that only marginally reduces cell survival in the absence of a sensitiser (Figure 4). It is believed that the cell kill is mediated by DNA strand breakage.
Details of the above results and experimental procedures are given in the non-limiting Examples which follow.
The following abbreviations are used:-
PBS phosphate buffered saline
EDTA ethylene diamine tetraacetic acid
Example 1 - (Figure 1) Mixtures containing pBR322 DNA (lμg) and various amounts of HPLC-purified iodoHoechst 33258, in 20μl of
5mM Tris (PM 7.5)/20mM NaCl/lmM EDTA were irradiated for
20 minutes in an open 1.5 ml Eppendorf tube under a UV-A lamp, at a measured fluence of 75μW cm-2 (UV Radiometer with UVX-36 detector; U.V. Products, Calif., USA). The samples were fractionated on 1.7% agarose gels containing ethidium bromide. Control samples (lanes 1 and 3) were not irradiated and kept in the dark. A further control was irradiated but did not contain iodoHoechst (lane 2). The final iodoHoechst concentrations in the samples were lμM (lane 4), 5μM (lanes 3 and 5) and 20μM (lane 6).
Example 2 - (Figure 2) EcoR1-cut pBR322 DNA was 5'-32P-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 lμM (lane 1), 2.5μM (lane 4), and 5μM (lanes 2 & 5), 10μM
(lane 6), 20μM (lane 7), and 40μM (lane 8). The samples with matched amounts of 32P were then analysed on a 16% polyacrylamide sequencing gel. Samples for lanes 1 and 2 were unirradiated controls and lane 8 was a Maxam-Gilbert
G+A track.
Example 3 - (Figure 3)
End-labelled restriction fragments were derived from pBR322. The 375 bp fragments were prepared by 3'- or 5'-32P end labelling at the EcoR1 site, followed by subsequent cleavage with BamHl and then isolation by preparative polyacrylamide gel electrophoresis.
Similarly, the 100bp fragments were obtained by
end-labelling at the Hind IV site and subsequent cleavage with Ddel and preparative electrophoresis. Samples of each of the four labelled fragments were mixed with carrier DNA and subjected to UV-A photolysis with 5μM iodoHoechst 33258 as described in Example 1. The samples were then analysed on 16% sequencing gels together with Maxam-Gilbert sequencing samples as in Example 1. In some cases (denoted pip+) the photolysed samples were subjected to treatment with 1M piperidine at 90°C for 30 minutes prior to sequencing gel analysis. The arrows indicate the sites of photolysis cleavage relative to Maxam-Gilbert references bands. The intensity of the bands vary considerably. The asterisked arrows denote particularly weak sites. The bp number in the pBR322 nucleotlde sequence is shown and the sequence is aligned with the zero in each number.
Example 4 - (Figure 4)
Mid-log phase V79 cells in 5ml alpha-MEM with 10% foetal calf serum in 25cm2 plastic flasks were incubated in the dark with 4μM iodoHoechst 33258 (HPLC purified) for 2 hours at 37°C and then chilled on ice for 30 minutes. The cultures were kept on ice during UV-A irradiation. The flasks were irradiated from above.
After allowing for attentuation by the flask and medium.
the dose-rate delivered to the monolayer was calculated to be approximately 50μW cm-2. After the appropriate irradiation time (0-20 minutes) the flasks were covered with black adhesive vinyl, washed twice with ice cold
PBS/EDTA and suspended with 2 ml, 0.01% Pronase. A portion of the cell suspension was washed twice with BSS, samples counted in a Coulter Counter, and various
aliquots plated-out in 50 mm plastic petri dishes. The colonies were fixed and stained after 7 days and the colonies of >50 cells scored. The control cloning efficiency (>60%) was used to calculate the relative cloning efficiency of treated cells. The data shown are derived from four separate experiments, indicated by different symbols. Open symbols depict controls without iodoHoechst 33258.
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). DNA
sequences are presented 5' to 3', left to right. In Figure 5, the cleavage site is underlined and its
position is given to the left of the DNA sequence. 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
[32P]dATP, dGTP and dCTP (which effectively labels the
synthesised strand at the 5'-end). This is followed by a chase with cold dATP and dTTP, which results in extensive synthesis of DNA - greater than 3000 bp.
Claims (24)
1. A radiosensitiser for use in cancer therapy which comprises a halogenated DNA ligand.
2. A radiosensitiser as claimed in Claim 1,
characterised in that the halogenated DNA ligand is a halogenated intercalating ligand.
3. A radiosensitiser as claimed in Claim 2,
characterised in that the halogenated intercalating ligand is a halogenated aminoacridine compound.
4. A radiosensitiser as claimed in Claim 1,
characterised in that the halogenated DNA ligand is a halogenated minor groove binding ligand.
5. A radiosensitiser as claimed in Claim 4,
characterised in that the halogenated minor groove binding ligand is a halogenated bis-benzimidazole compound.
6. A radiosensitiser as claimed in Claim 5,
characterised in that the halogenated bis-benzimidazole has the general formula:
wherein R1, R2, R3, R4 and R5, which are either the same or different, are selected from hydrogen, halogen, hydroxy, alkoxyl, nitro or any other suitable non- deleterious substituent; and R6 is alkyl; phenyl; phenyl optionally substituted with halogen, hydroxy, alkoxy, nitro or any other
suitable non-deleterious substituent; phenylalkyl; or phenylalkyl optionally substituted with halogen, hydroxy, alkoxy, nitro or any other suitable non-deleterious substituent.
7. A radiosensitiser as claimed in Claim 6,
characterised in that in the compound of formula (I)
R1, R2, R3, R4 and R5, which are either the same or different, are selected from hydrogen, hydroxy, alkoxy, iodo and bromo; and
R6 is methyl, phenyl or phenylalkyl.
8. A radiosensitiser as claimed in any one of the preceding claims, characterised in that the halogenated ligand is bound 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.
9. A method for enhancing the susceptibility of DNA to radiation damage, which comprises causing or allowing a halogenated DNA ligand to bind to the DNA before
subjecting the DNA or the locus thereof to ionising or ultraviolet radiation.
10. A method as claimed in Claim 9, characterised in that the halogenated DNA ligand is a halogenated
intercalating ligand.
11. A method as claimed in Claim 10, characterised in that the halogenated intercalating ligand is a
halogenated aminoacridine compound.
12. A method as claimed in Claim 9, characterised in that the halogenated DNA ligand is a halogenated minor groove binding ligand.
13. A method as claimed in Claim 12, characterised in that the halogenated minor groove binding ligand is a halogenated bis-benzimidazole compound.
14. A method as claimed in Claim 13, characterised in that the halogenated bis-benzimidazole has the general formula:
wherein R1, R2, R3, R4 and R5, which are either the same or different, are selected from hydrogen, halogen, hydroxy, alkoxy, nitro or any other suitable non-deleterious substituent; and R6 is alkyl; phenyl; phenyl optionally substituted with halogen, hydroxy, alkoxy, nitro or any other
suitable non-deleterious substituent; phenylalkyl; or phenylalkyl optionally substituted with halogen, hydroxy, alkoxy, nitro or any other suitable non-deleterious substituent.
15. A method as claimed in Claim 14, characterised in that in the compound of formula (I) R1, R2, R3, R4 and R5, which are either the same or different, are selected from hydrogen, hydroxy, alkoxy, iodo and bromo; and
R6 is methyl, phenyl or phenylalkyl.
16. A method as claimed in any one of Claims 9 to 15, characterised in that the halogenated ligand is bound 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.
17. 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.
18. A method as claimed in Claim 17, characterised in that the halogenated DNA ligand is a halogenated
intercalating ligand.
19. A method as claimed in Claim 18, characterised in that the halogenated intercalating ligand is a
halogenated aminoacridine compound.
20. A method as claimed in Claim 17, characterised in that the halogenated DNA ligand is a halogenated minor groove binding ligand.
21. A method as claimed in Claim 20, characterised in that the halogenated minor groove binding ligand is a halogenated bis-benzimidazole compound.
22. A method as claimed in Claim 21, characterised in that the halogenated bis-benzimidazole has the general formula:
wherein R1 , R2, R3, R4 and R5, which are either the same or different, are selected from hydrogen, halogen, hydroxy, alkoxy, nitro or any other suitable non-deleterious substituent: and
R6 is alkyl; phenyl; phenyl optionally substituted with halogen, hydroxy, alkoxy, nitro or any other
suitable non-deleterious substituent; phenylalkyl; or phenylalkyl optionally substituted with halogen, hydroxy, alkoxy, nitro or any other suitable non-deleterious substituent.
23. A method as claimed in Claim 22, characterised in that in the compound of formula (I)
R1, R2, R3, R4 and R5, which are either the same or different, are selected from hydrogen, hydroxy, alkoxy, iodo and brpmo; and
R5 is methyl, phenyl or phenylalkyl.
24. A method as claimed in any one of Claims 17 to 23 characterised in that halogenated ligand is bound 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU54167/90A AU639920B2 (en) | 1989-03-31 | 1990-03-30 | Halogenated dna ligand radiosensitisers for cancer therapy |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU346889 | 1989-03-31 | ||
| AUPJ3468 | 1989-03-31 | ||
| AU54167/90A AU639920B2 (en) | 1989-03-31 | 1990-03-30 | Halogenated dna ligand radiosensitisers for cancer therapy |
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| Publication Number | Publication Date |
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| AU5416790A AU5416790A (en) | 1990-11-05 |
| AU639920B2 true AU639920B2 (en) | 1993-08-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| AU54167/90A Ceased AU639920B2 (en) | 1989-03-31 | 1990-03-30 | Halogenated dna ligand radiosensitisers for cancer therapy |
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| Country | Link |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1988007986A2 (en) * | 1987-04-17 | 1988-10-20 | Ire-Celltarg S.A. | Compounds useful particularly for radiotherapy or imaging of cancer |
-
1990
- 1990-03-30 AU AU54167/90A patent/AU639920B2/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1988007986A2 (en) * | 1987-04-17 | 1988-10-20 | Ire-Celltarg S.A. | Compounds useful particularly for radiotherapy or imaging of cancer |
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| AU5416790A (en) | 1990-11-05 |
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