WO2001005439A9 - Radiodetection de proliferation cellulaire aberrante et therapie contre cette proliferation - Google Patents

Radiodetection de proliferation cellulaire aberrante et therapie contre cette proliferation

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Publication number
WO2001005439A9
WO2001005439A9 PCT/US2000/019250 US0019250W WO0105439A9 WO 2001005439 A9 WO2001005439 A9 WO 2001005439A9 US 0019250 W US0019250 W US 0019250W WO 0105439 A9 WO0105439 A9 WO 0105439A9
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WO
WIPO (PCT)
Prior art keywords
cells
compound
formula
radioactive atoms
deoxyuridine
Prior art date
Application number
PCT/US2000/019250
Other languages
English (en)
Other versions
WO2001005439A1 (fr
Inventor
Amin I Kassis
S James Adelstein
Original Assignee
Harvard College
Amin I Kassis
S James Adelstein
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 Harvard College, Amin I Kassis, S James Adelstein filed Critical Harvard College
Publication of WO2001005439A1 publication Critical patent/WO2001005439A1/fr
Publication of WO2001005439A9 publication Critical patent/WO2001005439A9/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers

Definitions

  • Embodiments of the present invention relate in general to methods and compounds useful for the detection and diagnosis of certain tissue conditions associated with rapidly dividing cells. Embodiments of the present invention also relate to methods and compounds useful in the detection and diagnosis of certain tissue conditions associated with the aberrant proliferation of cells, such as tumors. More particularly, embodiments of the present invention include the use of compounds readily taken up by rapidly dividing cells and which localize within such rapidly dividing cells and which can be used to detect, diagnose and/or treat tissue conditions associated with the rapidly dividing cells. Even more particularly, embodiments of the present invention relate to the intravenous administration and localization of certain compounds within certain tissue without substantial degradation of the compounds prior to localization.
  • nucleosides to treat and/or diagnose tissue conditions such as tumors. See US Patent Nos. 5,077,034, 5,094,835 and 5,308,605 hereby incorporated by reference in their entireties for all purposes.
  • Nucleoside compounds are typically labeled with an effector group such as a diagnostic or therapeutic moiety and administered to a patient.
  • the nucleoside compounds are incorporated into DNA during the synthetic phase of the cell cycle.
  • the incorporated nucleoside is retained for the life of the cell or its progeny.
  • the cells are then able to be detected, diagnosed or treated depending upon which type of effector group is chosen to be attached to the nucleoside.
  • an effector compound i.e. a compound including an effector group such as a diagnostic or therapeutic moiety
  • the target tissue should be approximately within an area that can be easily accessed
  • the agent once within the vicinity of the target tissue, the agent (a) freely diffuses throughout all the target tissue, (b) is innocuous outside of the cells of the target tissue, and (c) is selectively taken up either passively or actively and indefinitely retained by the cells of the target tissue, (3) once the effector compound has diffused out of the target area, it must either be converted quickly into an inactive, i.e., nontoxic, form and/or be excreted from the body, and (4) the biologic behavior of the effector compound is not altered by repeated injection, i.e., it lends itself to repeat/continuous injections.
  • radiolabeled IudR iododeoxyuridine
  • the use of a specific prior art compound in vivo i.e. radiolabeled IudR (iododeoxyuridine) presents a number of challenges.
  • the first relates to the matter of achieving therapeutic ratios in cancer cells, especially in the face of efficient hepatic dehalogenation (with a typical half-life being approximately a few minutes or less).
  • the second relates to the uptake of such radiopharmaceuticals by actively proliferating normal cell renewal systems (bone marrow, gut) and the consequent possible production of toxic side effects.
  • a third challenge is one shared with other cycle-dependent drugs and relates to the matter of labeling the entire tumor population: like many cycle-dependent agents, IUdR can only label cells in S-phase.
  • One effort to meet the above challenges has been locoregional drug administration.
  • Locoregional administration was further examined in a study in which patients suspected of having primary gliomas were given a single intracerebral injection of l23 IUdR. Scintigraphic imaging shows that the distribution of radiolabeled IUdR is very similar to that observed in the tumor-bearing rat studies described above, i.e. radioactivity is apparent mainly in the tumor, stomach, and bladder.
  • Radiolabeled IUdR has been instilled intravesically into the bladder of rats bearing bladder tumors and showed that (a) scintigraphic detection of bladder tumors is achieved with high sensitivity and specificity (virtual absence of radioactivity within the bladders of nontumor-bearing rats while the only visible area of activity remaining in the tumor-bearing animals is over the bladder region), (b) favorable tumor to normal tissue ratios are obtained, (c) IUdR uptake is detected at a very early stage of tumor development (hyperplasia stage), and (d) autoradiography demonstrates the DNA incorporation of radiolabeled IUdR into tumor cells and its absence from normal urothelium and other normal dividing tissues.
  • the methods of the prior art administer radioactively-labeled nucleotides, such as l23 IUdR, by locoregional injection/infusion, i.e., by modes other than intravenous administration primarily because of the identified problem of degradation of the compounds (prior to effective uptake by proliferating cells) by enzymes associated with the circulatory system.
  • Nucleoside compounds introduced into the circulatory system are rapidly catabolized to inert or harmless compounds by post-aortic enzymes such as those found in the liver thereby reducing the amount of compound available for uptake by proliferating cells.
  • Prior art methods of intra-arterial administration of a nucleoside are useful to treat, detect or diagnose proliferating cells where the cells are upstream of the liver. The nucleoside is effectively degraded by the liver and so is effectively unavailable for uptake into proliferating cells found downstream of the liver.
  • Embodiments of the present invention are based on the discovery that effector compounds, i.e. compounds including a diagnostic and/or therapeutic moiety, normally susceptible to degradation by enzymes associated with the circulatory system can be advantageously administered intravenously and can localize in proliferating cells in effective diagnostic or therapeutic amounts.
  • Effector compounds within the scope of the invention include those that are susceptible to degradation by enzymes associated with the circulatory system and include nucleoside-based compounds and analogs thereof including an effector group, such as a radionuclide moiety.
  • an effector compound is administered intravenously to a mammal, including a human patient, and the effector compound contacts proliferating cells prior to contacting an enzyme associated with the circulatory system that degrades the administered effector compound.
  • the proliferating cells are characterized in that they are perfused by the drug-laden blood prior to its passage through the systemic circulation, such as when the proliferating cells are perfused by pre-aortic blood as opposed to post-aortic blood.
  • the administered effector compound is selectively taken up by the proliferating cells, as compared to nonproliferating cells, in an effective diagnostic or therapeutic amount.
  • the diagnostic moiety or agent is then detected and optionally measured.
  • the therapeutic moiety or agent treats the cell in a manner to reduce or eliminate further growth or proliferation.
  • a systemically administered effector compound is used to target DNA-synthesizing cells.
  • the DNA-synthesizing cells are characterized in that they are perfused by pre-aortic blood as opposed to post-aortic blood.
  • the effector compound is selectively taken up by the DNA-synthesizing cells prior to degradation by enzymes associated with the circulatory system.
  • Embodiments of the present invention are advantageous in that they provide methods for diagnosing or treating proliferating cells perfused with pre-aortic blood which are more effective than existing methods.
  • the methods of the present invention provide for advantageous uptake and selectivity while avoiding disadvantageous degradation of the administered diagnostic or therapeutic agent.
  • One object of the present invention therefore, is to improve the efficiency of uptake of effector compounds and, therefore, diagnostic or therapeutic agents, into proliferating cells characterized in that they are perfused with pre-aortic blood.
  • Another object of the present invention is to utilize an intravenous mode of administration to diagnose or treat conditions associated with cell proliferation using compounds normally degraded by enzymes associated with the circulatory system.
  • Another object of the present invention is to provide a method of selectively introducing a diagnostic or therapeutic agent to proliferating cells as compared to surrounding non-proliferating cells.
  • Fig. 1 is a graph of the biodistribution of radioactivity in mice bearing subcutaneous
  • Fig. 2 is a graph of tumor/normal tissue ratios in mice bearing subcutaneous LS174T tumors 24 hours post 125 IUdR intravenous injection.
  • Fig. 3 is a graph of the biodistribution of radioactivity in mice bearing 2-week-old lung metastases from LS174T human tumor cells 24 hours post 125 IUdR intravenous injection.
  • Fig. 4 is a graph of tumor/normal tissue ratios in mice bearing 2-week-old lung metastases from LS174T human tumor cells 24 hours post l25 IUdR intravenous injection.
  • Fig. 5 is_a graph of the biodistribution of radioactivity in mice bearing 3-week-old lung metastases from LS174T human tumor cells 24 hours post 125 IUdR intravenous injection.
  • Fig. 6 is a graph of tumor/normal tissue ratios in mice bearing 3-week-old lung metastases from LS174T human tumor cells 24 hours post 125 IUdR intravenous injection. DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS
  • the principles of the present invention may be applied with particular advantage to obtain methods for selectively administering effector compounds that include diagnostic and/or therapeutic moieties to cells which are characterized in that they divide and/or proliferate at a rate greater than surrounding cells.
  • the effector compounds are taken up by the rapidly dividing cells during DNA-synthesis.
  • Common to all cells which rapidly divide, whether cancerous or not, is the process of DNA synthesis and the uptake of certain compounds, such as nucleosides, nucleotides and analogs thereof.
  • the present invention includes all cell types which rapidly divide and are capable of incorporating the effector compound into their DNA during DNA synthesis and cell division.
  • tumor cells i.e.
  • IUdR is a thymidine (TdR) analog in which the 5 -methyl group of TdR is replaced by iodine. Since the 5-methyl group and the iodine atom have similar van der Waals' radii, the substituted compound behaves remarkably like TdR.
  • TdR and IUdR are phosphorylated by thymidine kinase to TdR-monophosphate (dTMP) and IUdR- monophosphate (IdUMP), respectively.
  • dTMP TdR-monophosphate
  • IdUMP IUdR- monophosphate
  • the former is then further phosphorylated in a stepwise fashion and is incorporated into the DNA.
  • IdUMP may either follow the fate of dTMP or be dehalogenated by thymidylate synthetase (TS) to dUMP which is further converted to dTMP via the "de novo" TS-catalyzed reaction.
  • TS thymidylate synthetase
  • IUdR is taken up by DNA-synthesizing cells at very high rates (10,000-20,000 molecules per second), and (ii) most of the DNA-incorporated IUdR is retained for the cell or its progeny.
  • the methods of the present invention include contacting rapidly dividing cells with an effector compound in an amount effective to diagnose or treat the cells.
  • the cells are characterized in that they are perfused with pre-aortic blood as distinguished from post-aortic blood.
  • the compounds are administered intravenously at a point upstream of the rapidly dividing cells.
  • the compounds are selectively taken up by aberrantly proliferating cells as opposed to surrounding cells which are non-proliferating.
  • the compounds then travel post- aorta and are degraded by enzymes such as those found in the liver.
  • Certain useful compounds according to the present invention include the small molecule compounds of formula I and their analogs
  • R is absent or OH;
  • R 2 is absent or phosphate;
  • R 3 is absent or phosphate;
  • R 4 is absent or phosphate, such that where R 2 , R 3 and R 4 is absent, then R, is OH;
  • R 5 is H, F, OH or phosphate;
  • ] is H, F, or OH;
  • R 7 is an effector moiety.
  • Effector moieties within the scope of the present invention include purines such as adenine or guanine or pyrimidines such as cytosine, uracil or thymine which have been modified according to methods well known in the art to include a particular diagnostic or therapeutic group.
  • Radioactive atoms that emit alpha, beta, gamma or positron particles.
  • the term "radio-detectable agent” refers to an agent or molecule that is radiolabeled with a gamma-, positron-, Auger electron-, beta-, or alpha-emitting isotope.
  • a "radio- detectable agent” can be an agent or molecule that is labeled with a non-radioactive atom that can be activated by neutron irradiation to emit an alpha particle or that can be activated by external beam photons to emit low-energy Auger electrons.
  • radioactive atoms within the scope of the present invention are characterized in that they emit particles having an energy sufficient to image photographic film commonly used with external body gamma camera imaging and/or positron emission tomography. Each of external body gamma camera imaging and/or positron emission tomography are methods well know to those of skill in the art.
  • Certain radioactive atoms useful within the scope of the present invention as diagnostic agents include "C, l3 N, l4 O, l5 O, l8 F, 75 Br, 76 Br, 77 Br, 80 Br, l22 I, l23 I, l24 I, 126 I and 13I I. It is to be understood that one of skill in the art would be able to readily identify additional radioactive atoms useful as diagnostic agents based upon the present disclosure.
  • Radioactive atoms within the scope of the present invention include radioactive atoms commonly used in radiotherapy. Certain radioactive atoms are characterized in that they emit low energy electrons, i.e. those having an energy between about 1 eV and about 1000 eV. Certain other radioactive atoms are characterized in that they emit medium or high energy electrons, i.e. those having an energy between about 1000 eV and about 2,000,000 eV. Certain radioactive atoms useful as therapeutic agents commonly decay by electron capture and/or internal conversion and, as a result, emit Auger, coster-kronig and/or super coster- kronig electrons. Certain other radioactive atoms are characterized in that they emit high energy alpha particles. Certain radioactive atoms useful within the scope of the present invention as therapeutic agents include 75 Br, 76 Br, 77 Br, 80 Br, 80m Br l23 I, ,25 1, 131 1, 2 "At, 212 Bi, and 213 Bi.
  • Therapeutic groups useful within the scope of the present invention also include non- radioactive groups that when irradiated with neutron irradiation result in capture of a neutron and emission of an alpha particle suitable for therapy. Such therapeutic groups include those commonly used with neutron capture therapy such as l0 B. Additional therapeutic groups useful within the scope of the present invention further include groups that can be activated by low-energy photons to release Auger electrons commonly known in the art as photon activation therapy. Such groups include 75 Br and 127 I.
  • the compound of Formula I or an analog thereof is prepared in a pharmaceutically acceptable vehicle and administered intravenously.
  • the compound contacts rapidly dividing cells characterized in that they are perfused with pre-aortic blood as opposed to post-aortic blood.
  • Pre-aortic blood refers to blood within the circulatory system upstream of the aorta and downstream of the liver.
  • Post-aortic blood refers to blood within the circulatory system downstream of the aorta and upstream of the liver.
  • the compound of Formula I is administered intravenously at a location such that the compound travels via the circulatory system to the heart, then to the pulmonary artery, perfuse the lungs, travel back through the pulmonary vein to the heart, and finally to the rest of the body through the aorta.
  • the compound of Formula I contacts rapidly dividing cells, for example in the form of a tumor, which may be present in the heart and/or lungs prior to degradation by the liver. In this manner, the compound of Formula I is readily taken up by the rapidly dividing cells in a diagnostically or therapeutically useful amount.
  • Formula I can be administered at any location intravenously depending upon the location of the desired target site of rapidly dividing cells. Accordingly, the present invention includes methods of detecting, diagnosing, and treating aberrant proliferating cells that are associated with cancers and other disease conditions anywhere within the circulatory system where the proliferating cells are characterized by being perfused with pre-aortic blood. It is to be understood that one of ordinary skill in the art will readily identify targeted cells within the scope of the present invention as those which are dividing at a rate in excess of normal cell division which include tumors and which may be associated with certain disease conditions. For example, coronary heart disease remains the leading cause of death in the United States and is responsible for more than 500,000 deaths annually. The underlying cause of coronary heart disease is coronary atherosclerosis.
  • cardiac allograft vasculopathy i.e., cardiac transplant atherosclerosis
  • cardiac transplant atherosclerosis a major cause of late death in cardiac transplant recipients.
  • cardiac allograft vasculopathy i.e., cardiac transplant atherosclerosis
  • the methods of the present invention comprise the direct intravenous administration of an effective amount of an antitumor therapeutic or diagnostic dose of radiolabeled nucleotide or nucleoside, such as that identified by formula I, and more specifically 5-iodo-2'-deoxyuridine ( 125 IUdR, 13l IUdR, or ,23 IUdR) or 5-astato-2'-deoxyuridine ( 2 "AtUdR).
  • the radiolabeled nucleotide/nucleoside is targeted to a diseased tissue in the patient whereby the diseased tissue contains an aberrant, DNA synthesizing cell population and is characterized by being perfused with pre-aortic blood.
  • Diseased tissue of this nature includes tumors and cells associated with the disease conditions described above, including but not limited to lung cancer, cancer metastases to the lung, coronary heart disease, atherosclerosis and restinosis.
  • the radionuclide may be detected and measured for diagnostic purposes.
  • the radionuclide may serve as a therapeutic agent through incorporation of an effective amount of the radionuclide into the DNA of the aberrant, proliferating cells, such that growth of the cells is inhibited.
  • Na 125 I (1-100 mCi) is added to a solution of Bu 3 SnUdR (lOO ⁇ g) in ethyl acetate (100 ⁇ l) along with 100 ⁇ l of a solution containing 30% hydrogen peroxide/acetic acid (1/3, v/v).
  • the mixture is vortexed for 15 seconds and 100 ⁇ l distilled water are added followed by 100 ⁇ l 0.1 N Hcl.
  • the solution is loaded onto a Sep-Pak C 18 cartridge (previously washed with 6 ml methanol followed by 3 x 6 ml water) and the cartridge is eluted with 1 ml water to obtain 125 IUdR.
  • the sample is diluted (1 : 1) in 2 x saline and sterilized, e.g. by filtration, prior to administration to a mammal. It is to be understood that one of skill in the art would be able to prepare other radiolabeled compounds of the present invention within the scope of formula I and their analogs based upon the disclosure presented herein.
  • the percent injected dose per gram (% ID/g) of l25 I in blood, tumor, and various tissues and organs was determined and tumor/normal tissue (T/NT) ratios were calculated.
  • % ID/g percent injected dose per gram
  • Fig. 1 the data indicate that ⁇ 1%> of the injected dose is present per gram of subcutaneous tumor.
  • Fig. 2 the T/NT ratios of many tissues are ⁇ 1.
  • the results of Fig. 1 and Fig. 2 confirm that compounds of the present invention administered intravenously are not significantly taken up into tumors that are perfused by post-aortic blood. While not wishing to be bound by scientific theory, it is believed that the compounds are degraded by passage through the liver prior to contact with the tumor tissue.
  • the animals were killed 24 hours later, the lungs inflated with 0.5 ml phosphate buffered formalin, the radioactivity associated with them and all other tissues was measured in a gamma counter, and the %> ID/g and T/NT ratios were calculated. Additionally, the lungs were sectioned (5- ⁇ m thick) and stained with H&E. Histology demonstrated the presence of tumor foci within each lung section from tumor-bearing animals (results not shown). Despite the fact that most of the lungs were devoid of tumor, the biodistribution studies, the results of which are shown in Fig.
  • mice bearing 3-week-old LS174T lung tumor metastases i.e. in these studies, the tumors are somewhat larger than the 2-week-old tumors
  • mice bearing 3-week-old LS174T lung tumor metastases were injected intravenously with 10 ⁇ Ci 125 IUdR 100 ⁇ l saline.
  • the animals were killed 24 hours later, and the radioactivity associated with the lungs and all other tissues was measured in a gamma counter, and the % ID/g and T/NT ratios were calculated.
  • the biodistribution studies the results of which are shown in Fig.

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Abstract

Cette invention concerne un procédé permettant de détecter la présence de cellules proliférant de manière aberrante dans un tissu non proliférant d'un mammifère. Cette invention concerne également des procédés permettant de diagnostiquer et de traiter des cellules proliférant de manière aberrante.
PCT/US2000/019250 1999-07-14 2000-07-14 Radiodetection de proliferation cellulaire aberrante et therapie contre cette proliferation WO2001005439A1 (fr)

Applications Claiming Priority (2)

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US14373699P 1999-07-14 1999-07-14
US60/143,736 1999-07-14

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TWI247609B (en) * 2001-01-23 2006-01-21 Nihon Mediphysics Co Ltd Agent for diagnosis of tissue proliferation activity or the treatment of proliferative disease
US7928210B2 (en) 2007-03-01 2011-04-19 Siemens Medical Solutions Usa, Inc. Nucleoside based proliferation imaging markers
GB0815831D0 (en) * 2008-09-01 2008-10-08 Imp Innovations Ltd Compounds

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US5171563A (en) * 1988-09-30 1992-12-15 Neorx Corporation Cleavable linkers for the reduction of non-target organ retention of immunoconjugates
US5308605A (en) * 1992-08-27 1994-05-03 The President And Fellows Of Harvard College Diagnosis of tumors with 5-radioiodo-2'-deoxyuridine
US5466679A (en) * 1993-05-17 1995-11-14 The Ohio State University Research Foundation Carboranyl uridines and their use in boron neutron capture therapy
US5720935A (en) * 1995-06-09 1998-02-24 President & Fellows Of Harvard College Rapid synthesis of radiolabeled pyrimidine nucleosides or nucleotides from stannyl precursors

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