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Treatment of Cancer with Phlorizin and Its Derivatives

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Treatment of Cancer with Phlorizin and Its Derivatives Europaisches Patentamt J) European Patent Office © Publication number: 0 291 151 Office europeen des brevets A1 EUROPEAN PATENT APPLICATION (^) Application number: 88302189.1 © int.Ci.4:A61K 31/70 (§) Date of filing: 14.03.88 ©> Priority: 18.03.87 US 27413 Applicant: LeVeen, Harry H. 321 Confederate Circle @ Date of publication of application: Charleston, SC 29407(US) 17.11.88 Bulletin 88/46 Applicant: LeVeen, Robert F. © Designated Contracting States: 312 Lombard Street OE FR GB GR IT NL SE Philadelphia Pennsylvania 19147(US) Applicant: Leveen, Eric G. 141 South Battery Charleston South Carolina 29401 (US) Inventor: LeVeen, Harry H. 321 Confederate Circle Charleston, SC 29407(US) Inventor: LeVeen, Robert F. 312 Lombard Street Philadelphia Pennsylvania 19147(US) Inventor: Leveen, Eric G. 141 South Battery Charleston South Carolina 29401 (US) Representative: McCall, John Douglas et al W.P. THOMPSON & CO. Coopers Building Church Street Liverpool L1 3AB(GB) ® Treatment of cancer with phlorizin and its derivatives. © Malignant, neoplastic cells are treated by inhibit- t—ing glucose transport into the cell by administering ^one or more compounds selected from phlorizin, phloretin, phlorizin glucoronide, 4-deoxyphloretin-2- iflD-glucose, and cytochalasin-B, preferably while con- r" currently administering adjunct therapy such as heat, ^radiation or chemotherapy. In this manner, the cells Ojare prevented from growing or repairing the damage M caused by the adjunct therapy, which can be admin- Qistered in dosages that would otherwise be non- lethal if used alone. Q. Ill Xerox Copy Centre 0 291 151 TREATMENT OF CANCER WITH PHLORIZIN AND ITS DERIVATIVES The present invention relates to a method, substantiation for the latter explanation that a great- compounds and compositions for inhibiting glucose er number of receptor sites are responsible. transport across cell membranes, and more specifi- The rate of glucose transport across cells has cally to a method, compounds and compositions been shown to be directly related to the growth by which the growth of malignant neoplastic cells 5 potential of the cell. Glucose is a requirement for can be halted and such cells kept from repairing energy needs related to synthesis, as well as for and rejuvenating themselves. In a preferred form actual structural requirements in the synthesis of the invention is particularly concerned with a com- macromolecules (J Nat Can Inst. 62:3, January bined treatment whereby malignant cells are made 1979). Because malignant cells exhibit an extensive more susceptible to lethal damage from exposure w augmentation of glucose transport, they are under- to otherwise non-lethal doses of energy and anti- standably much more sensitive to drugs which tumor agents. inhibit glucose transport than are normal cells. The Researchers have long sought for a biochemi- magnitude of abnormal carbohydrate metabolism of cal difference by which malignant cells could be malignant cells increases the competition for glu- distinguished from normal cells. The work of War- 15 cose which develops between rapidly growing tu- burg in the early part of the twentieth century mors and the host's normal cells. Warburg men- (Warburg, The Metabolism of Tumors, Richard R. tions that the glycolysis of tumor cells can be so Smith & Co., New York, 1931) focused attention on rapid as to reduce the blood sugar in diabetic the differences in the way that cancer cells metab- patients. For example, the blood sugar concentra- olize glucose. Using a concept advanced by Pas- 20 tion in rats with a rapidly growing sarcoma remains teur, Warburg considered that cancer cells ferment normal until the tumor/body weight ratio increases while normal cells respire. The arguments ad- above .15. At ratios of .31 or greater, hypol- vanced by Warburg (Annual Review of Biochem- glycemia occurrs. Liver glycogen declines at high istry. 33:1, 1964) seemed to characterize the ma- tumor/body weight ratios. Gluconeogenesis from jority of rapidly growing malignant cells, and the 25 lactate increases thirty fold over autogenous occasional instance where the metabolism of the gluconeogenesis from endogenous alanine (Cancer tumor does not strictly fit Warburg's criteria is Res. 40:1699, 1980). Similar findings have been limited to very slow growing cancers which do not made in patients with rapidly progressive malignant produce death by cachexia and widespread metas- disease (Cancer Res. 39:1968, 1979; Cancer 33:66, tasis. 30 1974). Obviously, cancers sequestrate glucose and However, some recent knowledge with respect glucose utilization in cancer patients is extremely to the regulation of the energy metabolism in the high. The high potential for the malignant tumor to cell was unknown to Warburg. For instance, the metabolize glucose has even caused it to be re- Crabtree effect (inhibition of respiration by ferred to as a glucose trap (Acta Chir Scan [Suppl] glycolysis) 'is observed in practically all cells 35 498:141, 1980). (Biochema et Biophysica Acta 591:209, 1980). The This excessive glucose turnover in malignant addition of glucose to anaerobic suspensions of patients has again focused attention on the role of glucose starved malignant cells causes a burst of glucose metabolism in cancer cachexia. One con- respiration and glycolysis with lactate production sequence of the anaerobic metabolism of glucose which results in an inhibition of both respiration and 40 is the release of lactate into the circulating blood. glycolysis to values below those observed prior to The lactic acid is transported to the liver by the the addition of glucose. circulating blood. The liver converts the lactic acid The rate limiting factor in glucose metabolism to glucose thus completing the Cori cycle. The which determines the quantity of lactate formed in conversion of lactate to glucose is energy consum- the cell has been shown to be dependent upon the es ing and has been estimated to account for 10% rate at which glucose is transported across the cell increase in energy expenditure (Cancer Res. membrane. This knowledge suggests that the bio- 37:2336, 1977). The production of lactate may be chemical defect in cancer cells does not reside in so excessive in patients with cancer that with im- fermentation or respiration; but, rather, the primary pairment of liver physiology as with extensive liver defect must be the increased rate of glucose trans- so metastasis, lactic acidosis may occur (Cancer port across the cell membrane. This must be re- 47:2026, 1981). The severe carbohydrate drain lated either to an enhancement of the transport causes excessive gluconeogenesis which further mechanism or an actual increase in the receptor depletes the cancer patient (SA Med. J. 59:518, sites for glucose transport which are present in the 1981) (Ann NY Acad Sci, 72:103, 1980). membrane of the cell wall; and there is excellent Glycogen synthesized from glucose is abun- 0 291 151 dantly stored in cancer ceils (Cancer 19:98, 1966); ceptor sites. Both compounds will inhibit glucose however, the glycogen content decreases during transport but it takes a higher concentration of the exponential phase of tissue growth. Brain tu- phlorizin in non sodium dependent transfer sites. mors for example contain five times as much gly- Because of its low toxicity and the fact that cogen as small mammals brains (J. Neurochem. 5 phlorizin is more water soluble it has been the drug 29:959, 1977). This further supports the concept of choice in spite of the fact that for some transfer that increased glucose transport is a significant sites phloretin may be more active. This has also requirement for the rapidly growing cancer cell. caused the does of phlorezin to sometimes be Slow growing tumors contain more glycogen than raised beyond the dosage indicating a complete more rapidly growing tumors which utilize the glu- 10 block of glucose transfer in the kidneys. Work on cose more swiftly (Can. Res. 41:1165, 1981). phloretin indicates that more water soluble deriva- These factors support the concept that cancer cells tives of phloretin are possible without the loss of transfer glucose more swiftly than do normal cells. pharmacological activity. These energy related revelations have also These compounds are especially effective in turned attention to the glucose metabolism of grow- 75 preventing glucose transport across malignant cell ing cancer cells as a mechanism for the control of membranes, thereby suppressing the growth of cancer growth. Lonidamine has been found to be a cancer especially when used in conjunction with selective inhibitor of aerobic glycolysis in urine chemotherapy, radiation, heat or other techniques. tumor cells (J Nat Can Ins. 66:497, 1981). Dactylirin The pharmaceutical composition according to the is a new antibiotic which has a potential anticancer 20 invention comprises phlorizin, its glucuronide, effect since it influences the energy yielding car- cytochalasin-B or 4-deoxyphloretin-2-D-glucose, bohydrate mechanisms which function in malignant preferably together with a pharmaceutically accept- cells (Can Res. 39:4242, October 1979). able carrier. These compositions may be solid or In accordance with the present invention a pro- liquid and can be used in forms currently used in cess and compositions are provided for treating 25 medicine such as tablets, capsules, syrups and malignant neoplasms such as cancers and sar- injectable preparations. Because of its poor absorp- comas in mammals by inhibiting glucose entry into tion, the compositions of the invention is preferably the malignant cell to thereby render the cell more administered parenterally, dissolved in a suitable susceptible to the injurious effect of chemotherapy, carrier such as 1/2 normal saline . Orally accept- radiation, heat or anoxia and prevent repair or 30 able carriers are those currently used in medicine growth of the cell. Glucose entry into the malignant such as calcium carbonate, starch, lactose, talc, cell is inhibited by administering effective amounts magnesium stearate, gum acacia, aqueous alcohol, of phlorizin, its glucuronide, 4-deoxyphoretin-2-D- glycol or oil solutions or suspensions.
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