WO1985002616A1 - Traitement de metastases - Google Patents

Traitement de metastases Download PDF

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Publication number
WO1985002616A1
WO1985002616A1 PCT/US1984/002038 US8402038W WO8502616A1 WO 1985002616 A1 WO1985002616 A1 WO 1985002616A1 US 8402038 W US8402038 W US 8402038W WO 8502616 A1 WO8502616 A1 WO 8502616A1
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WO
WIPO (PCT)
Prior art keywords
forskolin
analogs
group
hydroxy
tumor
Prior art date
Application number
PCT/US1984/002038
Other languages
English (en)
Inventor
Kailash C. Agarwal
Robert E. Parks, Jr.
Original Assignee
Brown University Research Foundation
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 Brown University Research Foundation filed Critical Brown University Research Foundation
Publication of WO1985002616A1 publication Critical patent/WO1985002616A1/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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom

Definitions

  • This invention concerns methods and compositions for the treatment of tumor-induced metastasis, in particular, hematogeneous metastasis.
  • the U. S. Government has rights in this invention pursuant to grants Nos. CA 13943 and CA 07340 provided by the U. S. Public Health Service.
  • the hematogeneous metastatic process begins with the detachment of tumor cells from the primary tumor followed by intravasation with direct shedding of tumor cells into circulation. Although most tumor cells in circulation are quickly destroyed by various mechanisms, a few viable cells may be arrested in the microva ⁇ culature or otherwise may adher to endothelial surfaces.
  • thrombotic material consisting of platelets, erythrocytes and fibrin. Thrombus formation appears to be a significant event in the establishment of tumor colonies in the capillary beds of various organs. Blood platelets also appear to play an important role in tumor metastasis; it has been demonstrated that many metastasizing tumor cell lines induce platelet aggregation both in vitro and in vivo. Furthermore, upon aggregation, platelets release a substance or substances which promote tumor growth.
  • anticoagulants and anti-aggregating agents such as heparin, warfarin (Hagmar and Norrby, Vol. 5 Int. J. Cancer, pp. 72-84, [1970]; Lione and Bosmann, Vol. 2 Cell Biol. Int. Res., pp. 81-86 [1972]; Hoover and Ketcham, Vol. 35 Cancer, pp. 5-14 [1975]); aspirin (Gasic et al., Lancet II, pp. 932-933 [1972]; Wood and Hilgard, Lancet II, pp. 1416-1416 [1972]; Hilgard et al., Vol.
  • PKI 2 prostacyclin 2
  • PKI 2 a potent inhibitor of platelet aggregation
  • Forskolin compounds are generally defined as labdane diterpenoids having the general formula:
  • R 1 is hydrogen or a hydroxy or alkoxy, sulfonate or carbonate group
  • R 2 is a hydroxy, carbonate, acetyl, or acetoxy or alkanoyl group
  • R 3 is a hydroxy, carbonate, acetyl or acetoxy group
  • R 4 is hydrogen or a hydroxy or alkoxy, sulfonate or carbonate group
  • R 5 is either double-bonded oxygen or separately bound hydrogen and hydroxy groups
  • R 6 is a lower alkene or oxygen.
  • the forskolin blocks human platelet aggregation (induced by a wide variety of aggregation stimulators) by stimulating membrane adenylate cyclase thereby increasing several-fold the intracellular concentrations of cyclic AMP and inhibiting the tumor cell-platelet interactions which seem to play a role in tumor metastasis.
  • Forskolin may be unique in its action and perhaps interacts directly with the catalytic subunit of adenylate cyclase.
  • forskolin's high activity coupled with its low toxicity suggest that it can be a highly effective agent in reducing metastasis.
  • forskolin analogs with similar properties include various modifications of the groups labeled R 1 to R 6 in formula I above.
  • the 6-hydroxy group may be acetylated.
  • the 7-acetyl group may be removed or replaced by r-alkaroyl or tosyl groups.
  • the delta 14 15 bond may be substituted by oxygen.
  • 6,7-dicarbonate may also be effective.
  • the 6-acetyl-7-deacetyl derivative also appears to be active as do compounds where the chain length of the 6-alkanoyl group is increased or diethylarainocthyl groups are introduced at the 1 -position.
  • 7-Deacetyl-11-deoxo-11 beta-hydroxyforskolin and 1-methyl-6 acetyl-7 deacetyl derivatives also appear to be pharmacologically active.
  • the forskolin compounds described above may be administered alone or in conjunction with other agents.
  • the forskolin compounds may be combined with nucleoside transport inhibitors which retard the uptake of adenosine by red blood cells and the like; such inhibitors include p-nitrobenzylthioinosine and dilazep.
  • Our compounds may also be combined with agents that block the action of cAMP phosphodiesterase in converting cAMP to AMP, such as theophylline analogs, or compounds that both inhibit nucleoside transport and block cAMP conversion, such as dipyridamole and its analogs (i.e., RA-233), oxagrelate and papaverine.
  • the forskolin compounds may be combined with other compounds that act upon adenylate cyclase in different fashions to create a synergistic effect; such compounds include adenosine analogs and prostacyclins.
  • Fig. 1 is a graph plotting in vitro human platelet aggregation induced by the melanoma cells.
  • A control
  • B after treatment of platelet-rich plasma with forskolin.
  • Figs. 2a-2d are photographs comparing representative lung specimens from forskolin-treated and untreated mice.
  • Example I A mouse melanoma subline, B16-F10, (highly metastatic to the lungs) was obtained from EG & G Mason Research Institute, Worcester, MA, and adapted to growth in cell culture. The cultured cells were harvested by 1 min of trypsinization (0.25% trypsin-0.1% EDTA) or with the use of a rubber policeman, washed gently three times with Hank's balanced salts solution (HBBS, free of Ca and Mg ++ ). The cell viability determined by Trypan Blue exclusion ranged from 70-95% in the separate experiments. Freshly drawn whole blood from healthy adult human donors was anticoagulated with heparin (5 units/ml). The donors had not ingested antiplatelet drugs for at least 10 days.
  • Platelet-rich plasma was separated by centrifugation of the whole blood and platelet aggregation was measured in PRP by recording the increase in light transmission after the addition of the tumor cells.
  • Washed B16-F10 cell suspensions (2 x 10 7 /ml) were treated with potato apyrase (1 unit/ml) for about 5 min to degrade exogenous adenine nucleotides. Fifty microliters of the cell suspension was then added to the platelet-rich plasma after an incubation of 5 min with (A) 5 microliters DMSO (10% in saline) (Control) or (B) 5 microliters forskolin (200 micro Molars in DMSO 10% in saline).
  • Fig. 1 shows that B16-F10 cells (2 x 10 6 /ml) induced human blood platelet aggregation after a lag of about 1 min. However, if the PRP was preincubated (5 min) with the low concentration of forskolin (2 micromolars), the tumor cell-induced platelet aggregation was strongly blocked.
  • Example II Intravenous tail vein injections of B16-F10 cells (2 or 3 x 10 5 cell/mouse) to C57BL/6 mice (5-8 weekB old, 6-9 mice/group), produced a large number of pulmonary tumor foci after 9 or 14 days. However, if the mice were treated with a single intraperitoneally dose of forskolin (82 micrograms/mouse, i.e. 4-5 mg/kg) given 30 or 60 min before the tumor cell injections, reductions in tumor colonization of greater than 70 percent were observed. Similar results were seen in three separate experiments. Washed B16-F10 tumor cells (2 or 3 x 10 5 ) in 100 microliters Hanks balanced salts solution were injected from the tail vein 60 min (Exp. 1) or 30 min (Exp.
  • Fig. 2 presents typical specimens of lungs from untreated and forskolin-treated mice of experiments 2 and 3. Examination under a dissecting microscope revealed that the tumor foci in the forskolin-treated mice were smaller and more superficial than in the untreated mice, which were larger and more deeply embedded. A summary of these experiments is provided in Table 1 below.
  • EXAMPLE IV The in vivo experimental procedure of Example II above was also repeated using a combination of forskolin and oxagrelate. Intraperitoneal injections of the combination (oxagrelate: 40-45 mb/kg and forskolin: 1-1.5 mg/kg) 30 minutes before tail vein injections of the B16-F10 tumor cells reduced tumor colonization in the lungs of the mice 40 to 70 percent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un procédé de réduction de l'incidence de métastases chez des patients victimes de tumeurs consiste à administrer de la forskoline ou ses analogues, puissants inhibiteurs de l'agglutination de thrombocytes. Les composés de forskoline sont définis généralement comme diterpénoïdes de labdane et présentent la formule générale (I). Ces composés peuvent être administrés seuls ou en combinaison avec d'autres inhibiteurs de l'agglutination de thrombocytes.
PCT/US1984/002038 1983-12-14 1984-12-13 Traitement de metastases WO1985002616A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US56118283A 1983-12-14 1983-12-14
US561,182 1983-12-14

Publications (1)

Publication Number Publication Date
WO1985002616A1 true WO1985002616A1 (fr) 1985-06-20

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Application Number Title Priority Date Filing Date
PCT/US1984/002038 WO1985002616A1 (fr) 1983-12-14 1984-12-13 Traitement de metastases

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EP (1) EP0167567A1 (fr)
WO (1) WO1985002616A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0189801A1 (fr) * 1985-01-26 1986-08-06 Hoechst Aktiengesellschaft Procédé pour la préparation des dérivés de forskolin au moyen de transformations microbiennes
US4724238A (en) * 1985-01-26 1988-02-09 Hoechst Aktiengesellschaft Method of treating inflammatory diseases with labdan derivatives
EP0287469A1 (fr) * 1987-04-15 1988-10-19 Roussel-Uclaf Assocation renfermant à titre de principes actifs, un analgésique central et la forskoline
EP0293814A1 (fr) * 1987-06-03 1988-12-07 Hoechst Aktiengesellschaft Nouveaux dérivés mono- et polyhydroxyacylés de labdanes polyoxygénés, procédé pour leur préparation et leur application comme médicaments

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0116713A1 (fr) * 1982-12-27 1984-08-29 Schering Corporation Dérivés de labdane, procédé pour leur préparation et compositions pharmaceutiques contenant des dérivés de labdane
WO1984004454A1 (fr) * 1983-05-16 1984-11-22 Univ Yale Composition et procede de traitement de glaucome

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0116713A1 (fr) * 1982-12-27 1984-08-29 Schering Corporation Dérivés de labdane, procédé pour leur préparation et compositions pharmaceutiques contenant des dérivés de labdane
WO1984004454A1 (fr) * 1983-05-16 1984-11-22 Univ Yale Composition et procede de traitement de glaucome

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Journal of Medicinal Chemistry, Vol. 26, 1983; (Washington, US) S. BHAT et al.: "The Antihypertensive and Positive Inotropic Diterpene Forskolin: Effects of Structural Modifications on its Activity", pages 486-492, see pages 486, 487, 488, table i, 489-491 *
Journal of the Medicinal Chemistry, Vol. 26, 1983; (Washington, US) K. SEAMAN et al.: "Structure-Activity Relationships for Activation of Adenylate Cyclase by the Diterpene Forskolin and Derivatives", pages 436-439, see pages 436, 437, table 1, pages 438-439 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0189801A1 (fr) * 1985-01-26 1986-08-06 Hoechst Aktiengesellschaft Procédé pour la préparation des dérivés de forskolin au moyen de transformations microbiennes
US4724238A (en) * 1985-01-26 1988-02-09 Hoechst Aktiengesellschaft Method of treating inflammatory diseases with labdan derivatives
EP0287469A1 (fr) * 1987-04-15 1988-10-19 Roussel-Uclaf Assocation renfermant à titre de principes actifs, un analgésique central et la forskoline
FR2613935A1 (fr) * 1987-04-15 1988-10-21 Roussel Uclaf Association renfermant a titre de principes actifs, un analgesique central et la forskoline
EP0293814A1 (fr) * 1987-06-03 1988-12-07 Hoechst Aktiengesellschaft Nouveaux dérivés mono- et polyhydroxyacylés de labdanes polyoxygénés, procédé pour leur préparation et leur application comme médicaments

Also Published As

Publication number Publication date
EP0167567A1 (fr) 1986-01-15

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