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WO1993007748A2 - Inhibition au laser de l'hyperproliferation cellulaire dans des muscles lisses - Google Patents

Inhibition au laser de l'hyperproliferation cellulaire dans des muscles lisses Download PDF

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Publication number
WO1993007748A2
WO1993007748A2 PCT/US1992/009149 US9209149W WO9307748A2 WO 1993007748 A2 WO1993007748 A2 WO 1993007748A2 US 9209149 W US9209149 W US 9209149W WO 9307748 A2 WO9307748 A2 WO 9307748A2
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WO
WIPO (PCT)
Prior art keywords
psoralen derivative
smooth muscle
angioplasty
psoralen
derivative
Prior art date
Application number
PCT/US1992/009149
Other languages
English (en)
Inventor
Kenton W. Gregory
R. Rox Anderson
Original Assignee
The General Hospital Corporation
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 General Hospital Corporation filed Critical The General Hospital Corporation
Publication of WO1993007748A2 publication Critical patent/WO1993007748A2/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen

Definitions

  • the field of the invention is inhibition of smooth muscle cell proliferation.
  • Smooth muscle cell hyperproliferation is one of the primary underlying caused of restenosis (re- obstruction of a vascular passage following vascular surgery) . Restenosis occurs within 6 months of nonsurgical revascularization in 15% to 43% of the cases (Block et al., in Coronary Heart Diseases: Prevention,. Complications , and Treatment , Connor et al., (eds) Lippincott, Philadelphia, pp. 405-418, 1985; Holmes et al., Am. J. Cardiol . 53:77c, 1984; Mabin et al.,
  • Circulation 71:754, 1985 Recurrent myocardial ischemia is observed in many patients suffering restenosis. Asymptomatic restenosis, which may result in sudden death is observed in some cases (Levine et al., Am. J " . Cardiol . 55:673, 1985). Restenosis is observed whether angioplasty is performed by balloon catheter, laser ablation, or thermal ablation.
  • the degree of restenosis may depend on the location and morphologic features of the original lesion, the degree of dilation during angioplasty, and the degree of damage to the arterial wall during angioplasty. While smooth muscle cell hyperproliferation is thought to be the primary cause of restenosis, unsuitable dilation during angioplasty, platelet activation, and coagulation activation may also be involved (Cos et al., Can . Med . ASSOC. J. 134:1129, 1986).
  • Endothelial desquamation caused by injury to the arterial wall may be an important factor in inducing restenosis.
  • the loss of endothelial cells exposes the underlying connective tissue to factors present in the blood, including platelet derived growth factor and other mitogens, which may be the proximal cause of smooth muscle cell hyperproliferation and concomitant extracellular matrix deposition.
  • Disruption of endothelium can also lead to platelet deposition and activation of the coagulation system, steps which can result in formation of an occlusive thrombus.
  • Heparin has been proposed as a treatment for restenosis. Heparin has been shown to reduce platelet accumulation on the denuded neointima (Mustard, Ann . R. Coll . Physicians Surg. Can. 14:22, 1981). A study found that intravenous heparin in doses large enough to cause continuous anticoagulation reduced myointimal thickening in rats whose carotid arteries had been injured (Clowes et al., Nature 265:625, 1977).
  • heparin inhibits smooth muscle cell proliferation which occurs after denudation of endothelium by air-drying the rat carotid artery; this effect does not depend on anticoagulant activity (Guyton et al., Circ. Res. 46:625, 1980) .
  • In vitro studies of cultured rat smooth muscle cells demonstrated that heparin, in either its high anticoagulant form or its non-anticoagulant form, significantly inhibits cell proliferation (Hoover et al., Circ. Res . 47:578, 1980).
  • Cilazapril an inhibitor of angiotensin-converting enzyme
  • Photoreactive psoralens which are used in the present invention described below, are known to intercalate in double-stranded DNA and, upon absorbing ultraviolet light, form covalent linkages to pyrimidine bases (monoadducts) and, less often, cross-linkages between pyrimidines on opposite strands (cross-links) .
  • This modification of DNA is thought to be the basis for the inhibition of DNA synthesis observed in several cell types upon irradiation in the presence of a photoreactive psoralen derivative.
  • Psoriasis is caused by hyperplasia of the epidermis, and the ability of light-activated psoralens to block DNA synthesis provides a rationale for the effectiveness of psoralens in treatment of this condition.
  • the invention features a method of inhibiting smooth muscle cell proliferation in a patient.
  • the method includes the steps of: (a) administering a photoreactive psoralen derivative to the patient so that the psoralen derivative is taken up by smooth muscle cells of the patient, and (b) irradiating the smooth muscle cells whose proliferation is to be inhibited with light, of an approprite wavelength for a period of time and at an intensity sufficient to inhibit proliferation.
  • the proliferation is caused by vascular injury; the proliferation is caused by vascular surgery; the proliferation is caused by angioplasty.
  • the angioplasty is balloon angioplasty; is laser angioplasty; and is mechanical angioplasty.
  • the psoralen derivative is monofunctional.
  • the monofunctional derivative is kallein, is 3-carbethoxypsoralen; is angelicin; and is an angular furocoumarin.
  • the psoralen derivative is bifunctional.
  • the bifunctional psoralen derivative is 8- methoxypsoralen; is 5-methoxypsoralen; and is trimethyl psoralen.
  • Photoreactive psoralen derivative is meant a compound having the basic furan ring structure of psoralen (7H-Furo[3,2-g] [l]benzopyran-7-one) and groups on this ring structure (e.g., at the 4, 5 or 8 positions) such that the molecule, upon exposure to light of an appropriate wavelength, can form a covalent bond with at least one pyrimidine.
  • monofunctional psoralen derivative is meant a psoralen derivative which can only form a DNA monoadduct, i.e., it can only be covalently bound to a single pyrimidine.
  • bifunctional psoralen derivative is meant a psoralen derivative having functional groups which form a monoadduct or a DNA cross-link, i.e., it can be covalently bound to two pyrimidine molecules simultaneously.
  • the method of the invention provides a treatment for inhibition of unwanted smooth muscle cell proliferation, e.g., inhibition of restenosis.
  • the method employs compounds that have been well studied and are know to be safe for treatment of other conditions.
  • the method also provides a means by which treatment can be specifically targeted to the regions requiring treatment.
  • Fig. 1 is a graph depicting the effect of ultraviolet light and 8-methoxypsoralen on thymidine uptake by hyperproliferative smooth muscle cells
  • Fig. 2 is a graph depicting the effect of ultraviolet light and 8-methoxypsoralen on succinate dehydrogenase activity of hyperproliferative smooth muscle cells.
  • the invention provides a method for reducing unwanted smooth muscle cell proliferation by means of light-activated drugs, psoralens.
  • psoralens As illustrated below, 8-methoxypsoralen, upon exposure to ultraviolet light, inhibits proliferation of hyperproliferative smooth muscle cells without decreasing cell viability.
  • psoralen derivatives and ultraviolet light can be used to suppress smooth muscle cell proliferation despite the presence of high concentrations of growth factors such as platelet-derived growth factor. Because inhibition of cell proliferation by psoralen persists for only several weeks, there should be few negative long term consequences of treatment according to the invention.
  • Smooth muscle proliferation is normally regulated by the endothelial layers covering the smooth muscle cells.
  • a number of psoralen derivatives are derived from plants and have long been used in combination with irradiation for the treatment of vitiligo and psoriasis in a technique known as photochemotherapy. In the absence of irradiation many psoralens are chemically and biologically inert.
  • Psoralen derivatives useful in the method of the invention are the photoreactive derivatives which, when irradiated with light in the violet to ultraviolet range (e.g. 210-410 nm) , will inhibit smooth muscle cell proliferation, and which are substantially inert physiologically in the absence of ultraviolet light.
  • the psoralen derivatives used in the method of the invention preferably have a therapeutic index for killing (toxicity of the psoralen derivative when irradiated at the therapeutic wavelength: toxicity of the psoralen derivative when not irradiated) of at least 500.
  • a therapeutic index for killing toxicity of the psoralen derivative when irradiated at the therapeutic wavelength: toxicity of the psoralen derivative when not irradiated
  • Psoralen derivatives which are known to photoreact with DNA and those derivatives known to be useful for treatment of psoriasis are potentially useful in the method of the invention.
  • Psoralen derivatives commonly used for photochemotherapy of psoriasis and vitiligo include methoxsalen (8-methoxypsoralen) , bergapten (5- methoxypsoralen) , and trioxsalen (4,5',8- trimethylpsoralen) (de Wolff et al., Clin . Pharmacokinetic ⁇ , 11:62, 1986; Gupta et al., J. Amer. Acad. Derm. 17:703, 1987).
  • a number of other psoralen derivatives (4 '-hydroxymethyl-4,5',8-trimethylpsoralen, 4'-methoxymethyl-4,5' ,8-trimethylpsoralen, and 4'- aminomethyl 4,5' ,8-trimethylpsoralen hydrochloride) are known to photoreact with nucleic acids (Issacs et al., supra) .
  • a convenient in vitro assay for DNA binding is described by Issacs et al. (Biochemistry 16:1058, 1977).
  • rules have been developed for identifying those psoralen derivatives likely to be photoreactive.
  • DMEM Dulbecco's Modified Eagle's Medium
  • 8-methoxypsoralen 8 ⁇ g/ml (dissolved in ethanol and then diluted with DMEM)
  • control cells received no treatment.
  • the cells were treated with 365 nm ultraviolet light at various intensities (1 kW solar simulator with copper and cobalt sulfate filters) for a period sufficient to deliver the appropriate dose of radiation (usually 1 sec-4 min) .
  • the 8-methoxypsoralen was removed after irradiation and replaced with DMEM including 20% fetal calf serum (to stimulate hyperproliferation) .
  • Cell proliferation was assayed 48 hours later by a thymidine uptake assay and by an MTT assay.
  • thymidine incorporation decreased with increasing irradiation energy.
  • Control cells irradiated with the highest energy light 200 J were unaffected.
  • Cell viability was determined 48 hours after irradiation using previously described assay for succinate dehydrogenase activity (J * . Immunol . Methods 89:271, 1986).
  • Fig. 2 succinate dehydrogenase activity of 8-methoxypsoralen treated cells was unaffected even at the highest irradiation energies. Therapy
  • a photoreactive psoralen derivative is administered prior to angioplasty and the area subjected to angioplasty or vascular surgery is then irradiated with light of a wavelength and intensity that will activate the particular psoralen derivative being used.
  • the administration of psoralen may be oral, intravenous or intracoronal. Local administration can be achieved using a fluid filled catheter for both irradiation (as described in Gregory et al., PCT Application PCT/US88/04740) and delivery of the psoralen derivative to the arterial region to be treated.
  • the dosage required depends on a number of factors, including the mode of administration, the concentration required for inhibition of smooth muscle cell proliferation, and the pharmacokinetic behavior of the particular psoralen derivative used.
  • the clinical pharmacokinetics of psoralen derivatives has been extensively studied (de Wolff et al., Clin . Pharmacokinetics 11:62, 1986).
  • the standard oral dosage of 8- methoxypsoralen is 0.5 to 0.7 mg/kg.
  • Irradiation of the area to be treated can be carried out in conjunction with angioplasty.
  • Wavelengths of 300-410 nm and fluences of up to 100 J/cm 2 may be used to irradiate psoralen treated cells for the purpose of inhibiting cell proliferation.
  • the light fluence used is an important consideration, and selection of an appropriate fluence depends on such factors as drug concentration, accessibility of the cells being irradiated, and whether the formation of primarily monoadducts or cross-links is desired.
  • psoralen concentrations in the range of 1 ig/ml it is possible to effectively inhibit cell proliferation using 330 nm light at fluences as low as 0.1 J/cm 2 .
  • the actual fluence required may be substantially higher since cells and other material interposed between the light source and the cells being targeted will absorb some of the energy.
  • the action spectra of many psoralens indicate that higher fluences are required when longer wavelength light is being used.
  • the effective dose for 380 nm light might be 1 to 10 J/cm 2 (or less) while higher fluences might be required at longer wavelengths.
  • Both monofunctional and bifunctional psoralen derivatives are useful in the method of the invention.
  • the bifunctional derivatives more effectively inhibit cell proliferation than the monofunctional derivatives since they can form DNA cross-links, as well as the less toxic DNA monoadducts.
  • Cross-link formation requires the absorption of two photons; absorption of the first photon leads to monoadduct formation while absorption of the second photon converts the monoadduct to a cross-link.
  • the wavelength required for conversion of the monoadduct to a cross-link is shorter than that required for formation of the monoadduct (380- 410 nm) .
  • Irradiation can be performed twice, once at a relatively long wavelength to form monoadducts and a second time at a shorter wavelength to form cross-links.
  • Drug concentration and fluence are important variables or determining the ratio of monoadduct to cross-link formation. When the drug concentration is relatively low, cross-link formation requires higher fluences since the probability of any one drug molecule absorbing two photons is lower than at higher drug concentrations.
  • it should be recognized longer wavelengths may cause fewer side effects and will generally penetrate deeper than shorter wavelengths. Thus, selection of an appropriate wavelength for irradiation must balance the desire to form more potent cross-links with the desire for effective penetration and safety.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/US1992/009149 1991-10-23 1992-10-22 Inhibition au laser de l'hyperproliferation cellulaire dans des muscles lisses WO1993007748A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US781,996 1977-03-28
US78199691A 1991-10-23 1991-10-23

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WO1993007748A2 true WO1993007748A2 (fr) 1993-04-29

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0579784A4 (fr) * 1991-04-09 1994-04-06 Indiana University Foundation
US5545569A (en) * 1993-05-13 1996-08-13 Neorx Corporation Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells
US6268390B1 (en) * 1991-09-27 2001-07-31 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US7094550B2 (en) 1993-05-13 2006-08-22 Neorx Corporation Method to determine TGF-beta
US7625410B2 (en) 2001-05-02 2009-12-01 Boston Scientific Scimed, Inc. Stent device and method
WO2010040803A3 (fr) * 2008-10-08 2010-06-03 Hospital Clinic I Provincial De Barcelona Substances bloquant les canaux kv1.3 destinées au traitement de maladies associées à une hyperplasie de l’intima
WO2016151483A1 (fr) * 2015-03-25 2016-09-29 Univerza V Ljubljani Dérivés du psoralène utilisés comme inhibiteurs non peptidiques de l'activité de type chymotrypsine de l'immunoprotéasome
EP3097108A4 (fr) * 2014-01-23 2017-10-18 Immunolight, LLC Utilisation de dérivés de psoralène et d'une polythérapie pour le traitement de troubles de la prolifération cellulaire

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0579784A4 (fr) * 1991-04-09 1994-04-06 Indiana University Foundation
US6268390B1 (en) * 1991-09-27 2001-07-31 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US5545569A (en) * 1993-05-13 1996-08-13 Neorx Corporation Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells
US7094550B2 (en) 1993-05-13 2006-08-22 Neorx Corporation Method to determine TGF-beta
US7625410B2 (en) 2001-05-02 2009-12-01 Boston Scientific Scimed, Inc. Stent device and method
WO2010040803A3 (fr) * 2008-10-08 2010-06-03 Hospital Clinic I Provincial De Barcelona Substances bloquant les canaux kv1.3 destinées au traitement de maladies associées à une hyperplasie de l’intima
US8629110B2 (en) 2008-10-08 2014-01-14 Hospital Clinic I Provincial De Barcelona Kv1.3 channel blocking substances for the treatment of diseases associated with intimal hyperplasia
EP3097108A4 (fr) * 2014-01-23 2017-10-18 Immunolight, LLC Utilisation de dérivés de psoralène et d'une polythérapie pour le traitement de troubles de la prolifération cellulaire
WO2016151483A1 (fr) * 2015-03-25 2016-09-29 Univerza V Ljubljani Dérivés du psoralène utilisés comme inhibiteurs non peptidiques de l'activité de type chymotrypsine de l'immunoprotéasome

Also Published As

Publication number Publication date
AU2919392A (en) 1993-05-21

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