WO1994017089A2 - Method for localising and measuring the proliferation of cancer and compositions for same - Google Patents

Method for localising and measuring the proliferation of cancer and compositions for same Download PDF

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Publication number
WO1994017089A2
WO1994017089A2 PCT/GB1994/000182 GB9400182W WO9417089A2 WO 1994017089 A2 WO1994017089 A2 WO 1994017089A2 GB 9400182 W GB9400182 W GB 9400182W WO 9417089 A2 WO9417089 A2 WO 9417089A2
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fluorinated
biologically active
patient
tftdr
analogue
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PCT/GB1994/000182
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French (fr)
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WO1994017089A3 (en
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Hilmark Meek Warenius
Raymond John Abraham
Philip Charles Bulman Page
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The University Of Liverpool
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations

Definitions

  • the present invention relates to a method for localising and/or measuring the proliferation of cancer and to compositions for use with said method, and more particularly, though not exclusively to the use of fluorinated analogues of biologically active molecules, such as, for example, trifluoromethyl deoxyuridilate (TFTdR) or trifluorothymidine in said method.
  • fluorinated analogues of biologically active molecules such as, for example, trifluoromethyl deoxyuridilate (TFTdR) or trifluorothymidine in said method.
  • tumour cell kinetics may be measured by 5-bromo-2*- deoxyuridine (BUdR) administered to the patient intravenously followed by delayed biopsy and flow cytometric analysis of the percentage of cells which stain fluorescently with a monoclonal antibody directed against BUdR.
  • BBUdR 5-bromo-2*- deoxyuridine
  • This technique has produced an improved understanding of the potential doubling times of human solid tumours which challenges the present conventional radiotherapeutic schedules which use overall treatment times of four to six weeks.
  • a method of localising and/or measuring the proliferation of human tumours non invasively in a patient prior to and/or during therapy characterised in that a y F fluo ⁇ nated analogue of a biologically active material is injected or otherwise applied to a patient and followed in the patient using NMR spectroscopy.
  • the fluorinated analogue of the biologically active material is a fluorinated DNA precursor such as for example trifluoro methyl deoxyuridilate (TFTdR) or Trifluorothymidine.
  • TFTdR trifluoro methyl deoxyuridilate
  • Trifluorothymidine a fluorinated DNA precursor such as for example trifluoro methyl deoxyuridilate (TFTdR) or Trifluorothymidine.
  • TFTdR is injected into a patient and followed using NMR spectroscopy.
  • the NMR graph indicates another peak, that of TFTdR triphosphate.
  • a method of indirectly measuring DNA polymerase activity at the site of a tumour characterised in that a biologically active molecule containing a 19 F atom is injected or otherwise applied to a patient and followed in the patient using NMR spectroscopy and the rate of disappearance or appearance of the 19 F peak is measured to provide an indication of tumour activity.
  • the method enables DNA polymerase activity-to be measured by the disappearance of the TFTdR triphosphate peak.
  • This activity can in turn be used to indicate the response an intact living tumour cells has to drug and/or radiation treatment.
  • a labelling index can be calculated showing the percentage of cells in division.
  • Fluorine is an extremely good NMR probe due to the intrinsic sensitivity of the F nucleus, the complete absence of any background signals in vitro and the large chemical shift range of ⁇ q the "F nucleus.
  • fluorinated compounds of interest should be relatively free within the cell so that their relaxation signal can be studied.
  • Appropriate fluorinated compounds which could satisfy this requirement include for example fluorinated steroids and related analogues e.g. oestrogens such as for example 2- and 4- fluoro-oestrane, 2- and 4 fluro - 17- oestradiol, and 2- and 4- fluoro- 17- ethynyloestradoil, antioestrogens, fluorinated phorbol esters or related compounds, progesterones, glucocorticoids, androgens, nucleosides such as for example the analogue of the pyr idines, 5- fluorouracil, 5-trifluoromethyl -2'-deoxyuridilate (TFTdR), or the CH2F or CHF2 analogues thereof, fluorinated porphyrins and other compounds used in photodynamic therapy.
  • fluorinated steroids and related analogues
  • Porphyrins themselves are already known to localise in cancers in patients and this property is used in photodynamic therapy. Fluorinated porphyrins might thus provide an excellent method of selectively localising cancers in patients.
  • the invention also provides for the use of fluorinated analogues of biologically active molecules in localising and/or measuring the proliferation of a tumour in a non invasive manner by utilising the NMR properties of the fluorinated analogue to detect the position and/or uptake of the analogue to thereby localise and/or measure the proliferation of the tumour.
  • composition consisting essentially of 1 1 J 9F TFTdR, the composition being adapted for only injectable administration to the exclusion of topical administration.
  • TFTdR the sole diagnostically or pharmaceutically active ingredient
  • a pharmaceutical composition comprising TFTdR and pyrozofurin would be excluded since pyrozofurin is a known pharmaceutically active ingredient.
  • the biological active molecule is TFTdR and the activity of a tumour is calculated by following the disappearance of the TFTdR triphosphate peak over a given time period, the disappearance of the peak being a measure of its incorporation into DNA and an indication of the tumour activity.
  • a cell line - MOLT-4 a human in vitro T- lymphoblastic cell line was grown under oxic conditions and incubated with 19 J F Trifluorothymidine
  • TFTdR at a concentration of 100 ug/ml for 15 minutes.
  • the cells were washed in fresh medium and stopped at
  • NMR graphs were obtained at 0, 20 and 40 minutes.
  • peak A is TFTdR. (Determined from the fact that if exogenous TFTdR is applied immediately prior to NMR scanning, peak A increases) , peak B is TFTdR triphosphate and peaks C and D are standards produced by sodium monofluorophosphate.
  • the progressive disappearance of peak B the TFTdR triphosphate with time (cf Figs. 1 - 3) can be explained by the TFTdR being converted rapidly to TFTdR triphosphate which is then incorporated into DNA by the action of DNA polymerase. As the 19 F nucleus is incorporated into DNA it looses its freedom and peak B disappears from the scan.
  • Fig. 4 shows a plot of nucleotide peak area vs time.
  • Example 1 Since many carcinomas grow under hypoxic conditions Example 1 was repeated with the cell line studied under hypoxic conditions (5% CO2).
  • Fig. 5 shows TFTdR (A) and TFTdR triphosphate (B) peaks at 10°C - 0 minutes.
  • Fig. 6 shows the peaks after 30 minutes at 37°C
  • Fig. 7 shows the peaks after 60 minutes at 37°C
  • Fig. 8 shows the peaks after 120 minutes at 37°C.
  • TFTdR triphosphate disappears two smaller peaks (E) and (F) can be seen. These are thought to be TFTdR monophosphate and TFTdR diphosphate respectively. Whilst the additional peaks may result from hypoxia, the disappearance of the TFTdR triphosphate peak enables DNA polymerase activity to be indirectly measured.
  • Fig. 9 shows a plot of nucleotide peak area vs time.
  • the areas under peak B of Figs. 5, 6, 7 and 8 were measured by integration of the signal.
  • the putative trifluorothymidine triphosphate peak B was compared to a sodium monofluorophosphate peak (not shown on Figs. 5 to 8) and its area plotted against time.

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  • Genetics & Genomics (AREA)
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Abstract

A method for localising and/or measuring the proliferation of cancer non invasively is disclosed in which a 19F analogue of a biologically active molecule, for example, trifluoromethyl deoxyuridilate or trifluorothymidine is injected into a patient and followed using NMR spectroscopy. Suitable composition for such applications are also disclosed.

Description

DESCRIPTION
METHOD FOR LOCALISING AND MEASURING THE
PROLIFERATION OF CANCER AND COMPOSITIONS FOR SAME
The present invention relates to a method for localising and/or measuring the proliferation of cancer and to compositions for use with said method, and more particularly, though not exclusively to the use of fluorinated analogues of biologically active molecules, such as, for example, trifluoromethyl deoxyuridilate (TFTdR) or trifluorothymidine in said method.
Despite the many advances of the past two decades, the management of modern cancer therapy is still frequently impeded by an inability to accurately define the local and metastatic extent of a tumour, measure its growth and ascertain its relative sensitivity to a given treatment. In addition the high metastatic rates in many cancers predicate a need for the development of systemic therapies with more accurate tumour localisation. These in turn will rely on an improved ability to define the local and metastatic extent, proliferation rate and therapeutic sensitivity of the tumour in the individual patient.
At present, assays aimed at determining cell proliferation and sensitivity to treatment require invasive techniques to remove pieces of viable tumour for subsequent laboratory tests. For example in vivo tumour cell kinetics may be measured by 5-bromo-2*- deoxyuridine (BUdR) administered to the patient intravenously followed by delayed biopsy and flow cytometric analysis of the percentage of cells which stain fluorescently with a monoclonal antibody directed against BUdR.
This technique has produced an improved understanding of the potential doubling times of human solid tumours which challenges the present conventional radiotherapeutic schedules which use overall treatment times of four to six weeks.
Other studies suggest that whilst more rapidly proliferating tumours should show greater benefit from short intensive courses of radiotherapy such as CHART (Continuous Hyperfractionated Accelerated Radiotherapy) than from protracted regimens, this approach may not be appropriate for more slowly proliferating tumours.
Despite the value of BRdU measurements, practical considerations, such as the inaccessibility of the majority of tumours to easy biopsy and the inability of a single pretreatment test to predict changes in tumour cell kinetics during subsequent treatment, make it unlikely that there can be widespread use of this technique to individualise treatment for the majority of patients.
It is thus an object of the present invention to provide a method of localising and measuring the proliferation of human tumours non invasively prior to and/or during therapy.
According to one aspect of the present invention there is provided a method of localising and/or measuring the proliferation of human tumours non invasively in a patient prior to and/or during therapy, characterised in that a y F fluoπnated analogue of a biologically active material is injected or otherwise applied to a patient and followed in the patient using NMR spectroscopy.
The term "otherwise applied" is intended to include other means of administration such as, for example, oral or topical administration.
Preferably the fluorinated analogue of the biologically active material is a fluorinated DNA precursor such as for example trifluoro methyl deoxyuridilate (TFTdR) or Trifluorothymidine.
Once introduced the i5F molecule can be followed.
In one embodiment TFTdR is injected into a patient and followed using NMR spectroscopy. As well as a TFTdR peak, the NMR graph indicates another peak, that of TFTdR triphosphate. By measuring the rate of disappearance of this TFTdR triphosphate peak or the appearance or disappearance of other compounds derived from the introduced 19 F molecule as it is metabolised and incorporated into DNA whereupon it can't be detected due to the fact it is no longer in a 'relaxed' state, the DNA polymerase activity can be indirectly measured which measurement can thus be used to give information on a tumours activity.
According to another aspect of the invention there is provided a method of indirectly measuring DNA polymerase activity at the site of a tumour characterised in that a biologically active molecule containing a 19F atom is injected or otherwise applied to a patient and followed in the patient using NMR spectroscopy and the rate of disappearance or appearance of the 19F peak is measured to provide an indication of tumour activity.
In other words, in one embodiment the method enables DNA polymerase activity-to be measured by the disappearance of the TFTdR triphosphate peak. This activity can in turn be used to indicate the response an intact living tumour cells has to drug and/or radiation treatment. Furthermore, by comparing the intensity of the exogenously administered TFTdR with endogenous signals in the tumour cells, such as those from P containing metabolites, proteins or other suitable nuclei, a labelling index can be calculated showing the percentage of cells in division.
Of course the use of NMR spectroscopy in the diagnosis and treatment of many types of cancer is well established. The great majority of these studies have, however, used either ■'"H or JJ-P NMR.
Only recently has the utility of fluorine NMR become recognised. Fluorine is an extremely good NMR probe due to the intrinsic sensitivity of the F nucleus, the complete absence of any background signals in vitro and the large chemical shift range of ι q the "F nucleus.
Thus, in a recent study Bruker Report, 1986,2,15 Hull showed that the detoxifying catabolism of the chemotherapeutic agent 5-fluorouracil (FU) proceeds via 5,6 dihydro 5 Fluorouracil (DHFU) to fluoro ureido propenoic acid (FUPA) and finally 5-Fluoro- alanine (FBAL) and these species could all be detected in the urine of the patient. Also these metabolites could be detected by 9F NMR in both the plasma and in excised tumour.
Neither Hulls study, nor others by McSheehy (Br J Cancer 60, 303-309, 1989 and NMR in Biomedicine 2, 4, 133-141, 1989) or Wolf (Magnetic Resonance Imaging, 5, 165-169, 1987) appreciated the potential of their studies, namely that appropriate fluorinated compounds, those with molecules whose nuclei give a good spectroscopy signal and which are in relatively high abundance in the site being studied as compared to background, can be utilised such that exogenously administered fluorinated compounds may be taken up by tumour cells in patients whereupon they can be studied by NMR to indicate the locality and proliferation of the tumour thereby giving valuable diagnostic information which can be used in the further treatment of the cancer.
The fluorinated compounds of interest should be relatively free within the cell so that their relaxation signal can be studied. Appropriate fluorinated compounds which could satisfy this requirement include for example fluorinated steroids and related analogues e.g. oestrogens such as for example 2- and 4- fluoro-oestrane, 2- and 4 fluro - 17- oestradiol, and 2- and 4- fluoro- 17- ethynyloestradoil, antioestrogens, fluorinated phorbol esters or related compounds, progesterones, glucocorticoids, androgens, nucleosides such as for example the analogue of the pyr idines, 5- fluorouracil, 5-trifluoromethyl -2'-deoxyuridilate (TFTdR), or the CH2F or CHF2 analogues thereof, fluorinated porphyrins and other compounds used in photodynamic therapy.
Porphyrins themselves are already known to localise in cancers in patients and this property is used in photodynamic therapy. Fluorinated porphyrins might thus provide an excellent method of selectively localising cancers in patients.
The invention also provides for the use of fluorinated analogues of biologically active molecules in localising and/or measuring the proliferation of a tumour in a non invasive manner by utilising the NMR properties of the fluorinated analogue to detect the position and/or uptake of the analogue to thereby localise and/or measure the proliferation of the tumour.
According to a further aspect of the invention, there is provided the use of 19F TFTdR for the manufacture of a medicament for use in a method of diagnosing the local and/or metastatic extent of a tumour.
According to a yet further aspect of the invention there is provided a composition consisting essentially of 1 1J9F TFTdR, the composition being adapted for only injectable administration to the exclusion of topical administration.
By consisting essentially, is meant the sole diagnostically or pharmaceutically active ingredient is TFTdR.
Thus, for example, a pharmaceutical composition comprising TFTdR and pyrozofurin would be excluded since pyrozofurin is a known pharmaceutically active ingredient.
It is still yet a further aspect of the invention to provide a method for determining non invasively, the effect a given cancer treatment is having on the cancer.
Accordingly there is provided a method of ascertaining the relative sensitivity of a cancer treatment by i .nj.ecti.ng or otherwise applying a
Figure imgf000008_0001
fluorinated analogue of a biologically active molecule to a patient and following the cell kinetics in a non invasive manner using NMR spectroscopy.
Preferably the biological active molecule is TFTdR and the activity of a tumour is calculated by following the disappearance of the TFTdR triphosphate peak over a given time period, the disappearance of the peak being a measure of its incorporation into DNA and an indication of the tumour activity. To demonstrate the utility of the invention the following in vitro and in vivo studies were conducted:
EXAMPLE I A non-invasive 1x;97F high resolution magnetic resonance study on the uptake of Trifluorothy idine was conducted.
A cell line - MOLT-4, a human in vitro T- lymphoblastic cell line was grown under oxic conditions and incubated with 19JF Trifluorothymidine
TFTdR at a concentration of 100 ug/ml for 15 minutes.
The cells were washed in fresh medium and stopped at
20 minute intervals by lysis in SDS/pronase buffer.
NMR graphs were obtained at 0, 20 and 40 minutes.
These graphs are shown in Figs. 1 - 3.
In each of Figs. 1 - 3 peak A is TFTdR. (Determined from the fact that if exogenous TFTdR is applied immediately prior to NMR scanning, peak A increases) , peak B is TFTdR triphosphate and peaks C and D are standards produced by sodium monofluorophosphate.
The progressive disappearance of peak B the TFTdR triphosphate with time (cf Figs. 1 - 3) can be explained by the TFTdR being converted rapidly to TFTdR triphosphate which is then incorporated into DNA by the action of DNA polymerase. As the 19F nucleus is incorporated into DNA it looses its freedom and peak B disappears from the scan.
Indeed, this progressive disappearance of peak B can be more clearly seen with reference to Fig. 4.
Fig. 4 shows a plot of nucleotide peak area vs time.
The area under each of peaks B and C of Fig. 1, 2 and 3 was measured by integration of the ^ F signal. The putative trifluorothymidine triphosphate peak B was compared to the sodium monofluoro phosphate peak C and its area plotted against time. The disappearance of the trifluorothymidine triphosphate peak could be observed and is believed to be due to the incorporation of the X 19JF tri.fluorothymidine into DNA.
Example 2.
Since many carcinomas grow under hypoxic conditions Example 1 was repeated with the cell line studied under hypoxic conditions (5% CO2).
The results are shown in Figs. 5 to 9.
Fig. 5 shows TFTdR (A) and TFTdR triphosphate (B) peaks at 10°C - 0 minutes.
Fig. 6 shows the peaks after 30 minutes at 37°C
Fig. 7 shows the peaks after 60 minutes at 37°C, and
Fig. 8 shows the peaks after 120 minutes at 37°C.
As peak B, TFTdR triphosphate, disappears two smaller peaks (E) and (F) can be seen. These are thought to be TFTdR monophosphate and TFTdR diphosphate respectively. Whilst the additional peaks may result from hypoxia, the disappearance of the TFTdR triphosphate peak enables DNA polymerase activity to be indirectly measured.
Finally, Fig. 9 shows a plot of nucleotide peak area vs time.
The areas under peak B of Figs. 5, 6, 7 and 8 were measured by integration of the
Figure imgf000010_0001
signal. The putative trifluorothymidine triphosphate peak B was compared to a sodium monofluorophosphate peak (not shown on Figs. 5 to 8) and its area plotted against time.
Example 3.
In order to determine the feasibility of in vivo detection a pilot experiment on CBA mice bearing RIF 1 tumours was carried out. Using doses of 60mg/kg TFTd R it was possible to detect approximately ImM concentration of TFTd R in 40 mg tumours. A typical i9F spectrum for such an experiment is shown in Fig. 10. The spectrum shown is that obtained when an anaesthetised CBA mouse was injected with 60mg/kg of trifluorothymidine intra peritoneally and studied. The large peak at about 63ppm is believed to be that of trifluorothymidine, approximate concentration ImM. By extrapolation with studies in which fluorouracil has been administered intravenously to patients it is predicted that TFTdR would be readily detectable in human tumours following intravenous administration of 600-700mg/πr. The lack of availability of an appropriate formulation for intravenous use clinically has prevented this further work up to the present time.

Claims

1. A method of localising and/or measuring the proliferation of human tumours non invasively in a patient prior to and/or during therapy, characterised in that a A F fluorinated analogue of a biologically active material is injected or otherwise applied to a patient and followed in the patient using NMR spectroscopy.
2. A method as claimed in claim 1 in which the biologically active material is applied by oral or topical administration.
3. A method as claimed in claim 1 or 2 in which the i9F fluorinated analogue of the biologically active material is a fluorinated DNA precursor. . A method as claimed in claim 3 in which the 9F fluorinated DNA precursor is trifluoromethyl deoxyuridilate (TFTdR) .
5. A method as claimed in claim 3 in which the F fluorinated DNA precursor is trifluorothymine
(TFT) (trifluoromethyluracil) .
6. A method as claimed in claim 1 or 2 in which the 9F fluorinated analogue of a biologically active material is a fluorinated compound in which the 1 19JF atom or atoms are relatively free such that the compound has a good relaxation signal.
7. A method as claimed in claim 6 in which the fluorinated compound is selected from fluorinated steroids and related analogues, fluorinated phorbol esters or related compounds, progesterones, glucocorticoids, androgens, nucleosides, fluorinated porphyrins and other compounds used in photodynamic therapy.
8. A method as claimed in claim 7 in which the fluorinated steroid is an oestrogen or related analogue.
9. A method as claimed in claim 8 wherein the oestrogen or related analogue is one selected from 2 fluoro-oestrane, 4 fluoro-oestrane, 2 fluoro 17 oestradiol, 4 fluro 17 oestradiol, 2 fluoro 17 ethynyloestradiol, 4 fluoro 17 ethynyloestradiol or an antioestrogen.
10. A method as claimed in claim 7 wherein the nucleoside is the analogue of one of the pyrimidines, 5-fluorouracil, 5 trifluoromethyl-2'-deoxyuridilate (TFTdR) or the CH2F or CHF2 analogues thereof.
11. The use of F trifluoromethyl deoxyuridilate (TFT dR) for the manufacture of a medicament for use in a method of diagnosing the local and/or metastatic extent of a tumour.
12. A composition consisting essentially of 19F trifluoromethyl deoxyuridilate (TFTdR) , the composition being adapted for only injectable administration to the exclusion of topical administration.
13. A method of ascertaining the relative sensitivity of a cancer treatment by injecting or otherwise applying 1A9JF fluorinated analogues of a biologically active molecule to a patient and following the cell kinetics in a non-invasive manner using NMR spectroscopy.
14. A method as claimed in claim 13 wherein the biologically active molecule is 19F trifluoromethyl deoxyuridilate (TFT dR) and the.disappearance of a TFT dR triphosphate peak is followed using NMR spectroscopy.
15. A method of indirectly measuring DNA polymerase activity at the site of a tumour characterised in that a biologically active molecule containing a 1i39F atom is injected or otherwise applied to a patient and followed in the patient using NMR spectroscopy and the rate of disappearance or appearance of the 1x F peak i.s measured to provide an indication of tumour activity.
16. A method as claimed in claim 15 in which the biologically active A 19JF molecule i•s trifluoromethyl deoxyuridilate (TRTdR) and the rate of disappearance of a TRTdR triphosphate peak is measured.
PCT/GB1994/000182 1993-01-30 1994-01-31 Method for localising and measuring the proliferation of cancer and compositions for same WO1994017089A2 (en)

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