United States Patent [19] [11] Patent Number: 4,898,732 Fernandez [45] Date of Patent: Feb. 6, 1990 [54] INHIBITING OF TUMOR GROWTH WITH Ischemia; American Journal of Physiology, vol. 243, AN ANTAGONIST OF THE pp. H869-H875, (1982). ' RENIN-ANGIOTEN-SIN SYSTEM Jane L. Frederick, MD. eta1., Initiation of Angiogene sis by Porcine Follicular Fluid, American Journal of [75] Inventor: Leonardo A. Fernandez, Guilford, Obstet Gynecol, Aug. 15, 1985, vol. 152, No. 8, pp. Conn. 1073-1078. [73] Assignee: The Clinipad Corporation, Guilford, Fernandez et al., Angiotensin II Decreases Mortality Conn. Rate in Gerbils with Unilateral Carotid Ligation, Stroke vol. 17, No. l, Jan-Feb., 1986, pp. 82-85. [21] Appl. No.: 190,158 Fernandez et al., Renin in Angiolymphoid Hyperplasia with Eosinophilia Arch. Pathol. Lab. Med., vol. 110, [22] .Filed: May 4, 1988 Dec., 1986, pp. 1131-1135. Fernandez et al., Neovascularization Produced by An [51] Int. Cl.4 ............................................ .. A61F 13/00 giotensin II, The Journal of Laboratory and Clinical [52] US. Cl. .................................. .. 424/422; 424/423; Medicine, vol. 105, No. 2, pp. 141-145, Feb., 1985. 424/426 Dominique Baruch et al., Diagnosis and Treatment of [58] Field of Search .................. .. 514/16, 17; 424/427, Renin-secreting Tumors, Report of Three Cases, Hy 424/428 pertension Case Reports, vol. 6, No. 5, Sep.-Oct., 1984, [56] References Cited pp. 760-766. Michael J. Peach, Renin-Angiotensin System: Bio U.S. PATENT DOCUMENTS chemistry and Mechanisms of Action, Physiological 3,932,624 1/1976 Fulton ................................. .. 514/16 Reviews, vol. 57, No. 2, Apr., 1977, pp. 313-370. 4,416,595 11/1983 Cromie .............................. .. 417/476 John B. Kostis et al., Angiotensin Converting Enzyme Inhibitors, Alan R. Liss, Inc., New York, pp. 213-261, OTHER PUBLICATIONS (1987). Dominic Bazuck et al., Diagnosis and Treatment of Primary Examiner-Thurman K. Page Renin-secreting Tumors, etc., vol. 6, No. 5, Sap-Oct. Assistant Examiner—Leon R. Horne 1984, pp. 760-766. Attorney, Agent, or Firm-Garrettson Ellis Product Information concerning enalapril maleate, pp. 1406 & 1407. [57] ABSTRACT Product Information concerning captopril, pp. A method of inhibiting tumor growth in a patient which 2046-2048. comprises administering to the patient an effective dose Diagnostic Product Information concerning saralasin of a pharmaceutical antagonist of the renin-angiotensin acetate, pp. 3011-3013. system of the patient. Leonardo A. Fernandez et al., Renin-angiotensin and Development of Collateral Circulation after Renal 7 Claims, 1 Drawing Sheet VASOTEC GROUP 80 RATESURVIVAL% ‘CONTROL GROUP l l O U1 6.. 15 2O 25 DAYS AFTER IMPLANT US. Patent Feb. 6, 1990 4,898,732 FIG. I I00 VASOTEC GROUP 80 m CONTROL GROUP DAYS AFTER IMPLANT 4,898,732 1 2 pril (sold under the trademark CAPT OTEN by INHIBITING OF TUMOR GROWTH WITH AN Squibb); and enalapril maleate (sold under the trade ANTAGONIST OF THE RENIN-ANGIOTEN-SIN mark VASOTEC by Merck, Sharp, and Dohme). Ac SYSTEM cording to published literature, enalapril maleate and captopril are indicated for use in the treatment of hyper BACKGROUND OF THE INVENTION tension. Both of the drugs are stated to act by suppress In the article by Leonardo A. Fernandez et al. enti ing the conversion of angiotensin I to the vasoconstric tled Renin-Angiotensin and Development of collateral tor substance, angiotensin II. Circulation After Renal Ischemia, AmJ. Physiol. 243 Saralasin acetate is indicated for use as a diagnostic (Hart, Circ. Physiol. 12) H869-H875, 1982, it is reported agent for the detection of angiotensin II-dependent that the infusion of angiotensin-II to aortic-ligated left hypertension, and is stated to act as an angiotensin II renoprival animals tends to restore blood ?ow to mus analog that binds to angiotensin II receptors, but is a less cle. From this, the article concludes that after renal effective vasoconstrictive agonist than angiotensin II. ischemia, the renin-angiotensin system, independent of Thus, saralasin acetate acts as an antagonist of angioten its hypertensive effect, restores blood flow by stimulat 5 sin II, lowering blood pressure. However, in the pres ing the development of collateral circulation. ence of low levels of circulating angiotensin II, saralasin The resin-angiotensin system is a well-known bio acetate can behave as an agonist, raising the blood pres chemical pathway in mammals, which is best known for sure. its effect on blood pressure. The renin-angiotensin sys Others of such pharmaceutical antagonists may also tem also governs the concentration of plasma aldoste be used in accordance with this invention; for example rone, through which intermediate the potent action of the'angiotensin converting enzyme inhibitors listed and angiotensin II may be effected. However, the exact mechanism of angiotensin II is not known, and the in discussed in the publication of John B. Kostis, M.D., et vention of this application is not intended to be limited a1 entitled Angiotensin Converting Enzyme Inhibitors, to any particular theory about mechanisms of operation. 25 published by Alan R. Liss, Inc. of New York, specifi Angiotensin II has been planted into avascular rabbit cally Alecepril, Cilazapril, Delapril, Fentiapril, Foseno cornea, and it has been demonstrated that this substance pril, Lisinopril, Pentopril, Perindopril, Pivalopril, strongly promotes local new blood vessel formation; Quinapril, Ramipril, Spirapril, Zofenopril, etc.. Fernandez, L. A. et al. Neovascularization Produced by The pharmaceutical antagonists of this invention may Angiotensin II, J. Lab. Clin. Med. 1985; 105:141-145; 30 be administered to a patient in any conventional manner Meade Twickler & Fernandez: Neovascularization Pro including orally, intravenously, by regional perfusion of duced by Angiotensin II. Fed. Proc. 1982; 41: 12-1230. an isolated appendage or organ by direct administration It is known that tumors have a capability of inducing through a medical pump directly to the tumor site (see the growth of surrounding vascular system to provide for example US. Pat. No. 4,416,595), or the like. Partic the tumor with an adequate supply of blood. In those ularly, one may implant in a patient a controlled release events where a supporting vascular system does not member of any known type, the member containing and grow, the size of the tumor is limited by the lack of a releasing in a controlled manner an effective dose of a supporting blood system. pharmaceutical antagonist of the renin-angiotensin sys It has been found that angiotensin II is a very potent tem of the patient. The controlled release member may angiogenic factor. It can elicit blood vessel growth in be implanted at a tumor site, thus causing the slow the rat cornea when present at extremely low concen release of the pharmaceutical antagonist for continuing trations. inhibition of the growth of vascularization in the patient DESCRIPTION OF THE INVENTION at least in an area 'adjacent the implanted controlled release member. The invention of this application relates to a method 45 A large number of controlled release members are of inhibiting tumor growth in a patient which carries at well known and described in the patent literature and least one tumor, which comprises administering to the elsewhere, and there is no intrinsic limitation against the patient an effective dose of a pharmaceutical antagonist of the renin-angiotensin system of the patient. Some use of the invention of this application in conjunction with any of them. Particularly, the pharmaceutical an tumors stimulate the growth of a supporting vascular system by the manufacture of renin, which is then pro tagonist of this invention may be dispersed into a con cessed through the renin-angiotensin system, with the trolled release member such as a small mass of silicone result that a supporting vascular system grows about rubber or a hydroxylated acrylate compound which is the tumor. In accordance with this invention, it has well known for use in contact with living cells, for been discovered that such tumors may have their 55 example the material sold as HYDRON plastic, or the growth inhibited by inhibition of the growth of the like. supporting vascular system for the tumor by the use of The respective dosages of the pharmaceutical antago an antagonist for the renin-angiotensin system of the nists used in this invention are typically the speci?c patient. recommended dosages in current use with respect to the The patient is desirably a human patient, but the in 60 specific embodiments of pharmaceutical antagonists vention is effective with respect to animals such as the listed above. The usual dosage ranges for human beings rat, which are intended to be included in the term “pa for these drugs are as follows: tient”. for enalapril maleate 10-40 mg. per day administered Pharmaceutical antagonists for the renin-angiotensin in a single dose or two divided doses; system are well-known. Speci?c pharmaceutical antag 65 for captopril, 25-50 mg. bid. or tid. but if necessary, onists which are currently available for use as drugs up to a maximum daily dose of 450 mg; include saralasin acetate, sold under the trademark for saralasin acetate, from 0.05 to 20 micro SARENIN by Norwich-Eaton Pharmaceuticals; capto grams/kg./min. 4,898,732 3 4 The published literature on these drugs should be hydroxylated acrylate plastic which contained an ex consulted, and the warnings about side effects and the tract from a human brain tumor (glioblastroma multi like should be carefully considered as these materials forme). The extract was incorporated into Hydron plas are used. tic dissolved in solution, with a known amount of said The above dosages are of course for a whole body solution pipetted into Teflon plastic molds and allowed treatment in accordance with this invention. If regional to dry overnight at 4 degrees C. to form a solid bead.