United States Patent [19]
`Sehgal et al.
`
`[54]
`
`[75]
`
`[73]
`
`[21]
`[22]
`
`[60]
`
`[51]
`[52]
`[58]
`
`USE OF RAPAMYCIN IN TREATMENT OF
`TUMORS
`Inventors: Surendra N. Sehgal, Princeton, N.J.;
`Claude Vezina, Oka, Canada
`Ayerst, McKenna & Harrison, Inc.,
`St. Laurent, Canada
`784,274
`Oct. 29, 1991
`
`Appl. No.:
`Filed:
`
`Assignee:
`
`Related U.S. Application Data
`Continuation-in-part of Ser. No. 682,813, Apr. 9, 1991,
`Pat. No. 5,066,493, which is a continuation-in-part of
`Ser. No. 391,334, Aug. 9, 1989, abandoned, which is a
`division of Ser. No. 592,193, Mar. 22, 1984, Pat. No.
`4,885,171, which is a continuation of Ser. No. 126,276,
`Mar. 3, 1980, abandoned, which is a continuation of
`Ser. No. 957,626, Nov. 3, 1978, abandoned.
`Int. Cl.” ..................... A61K 35/00; A61K 31/66;
`A61K 31/505; A01N 57/00
`U.S. C. .................................... 424/122; 514/110;
`514/274; 514/291
`Field of Search ................ 424/122; 514/110, 274,
`514/291
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,929,992 2/1976 Sehgal ................................. 424/122
`3,993,749 11/1976 Sehgal .....
`.... 424/122
`4,316,885 3/1982 Rakhi ......
`.... 424/122
`4,401,653 8/1983 Eng .................
`.... 424/114
`4,650,803 3/1987 Stella et al. ..........."-------------- 514/291
`
`II.I.I.I.I.I.I.I.IIII
`
`US005206018A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,206,018
`Apr. 27, 1993
`
`
`
`4,885,171 12/1989 Surendra et al. ................... 424/122
`5,066,493 11/1991 Sehgal ..................
`... 424/122
`5,078,999 1/1992 Warner ....
`... 424/122
`5,080,899 1/1992 Sturm .................................. 424/122
`OTHER PUBLICATIONS
`patent application. Ser. No. 07/717,773 filed Jun.
`U.S.
`18, 1991—(Miller).
`Abst. dist. at Fifth Intl Conf. of Inflamm. Res. Assoc.
`121, Sep. 23, 1990 (Baeder, W. L.).
`Vezina, C. J. Antibiot. 28, 721–726 (1975).
`Sehgal, S. J. Antibiot. 28, 727–732 (1975).
`Martel. R., Can J. Physiol. Pharmacol., 55, 48 (1977).
`Eng. C. J. Antibiotics 37:1231 (1984).
`FASEB 3:3411 (1989)—(Staruch, M. J.).
`FASEB 3:5256 (1989)—(Dumont, F. J.).
`Med. Sci. Res. 17:877 (1989)–(Morris, R).
`Primary Examiner—Nathan M. Nutter
`Attorney, Agent, or Firm—Arnold S. Milowsky
`[57]
`ABSTRACT
`This invention provides a method of treating, inhibiting
`the proliferation of, reducing the size of, or eradicating
`malignant neoplasms in a mammal in need thereof
`which comprises administering an antineoplastic
`amount of rapamycin to said mammal. In particular,
`rapamycin is useful in treating, inhibiting the prolifera
`tion of, reducing the size of, or eradicating malignant
`mammary and skin carcinomas, and central nervous
`system neoplasms.
`
`12 Claims, No Drawings
`
`Ex. 1063-0001
`
`

`
`1
`
`20
`
`25
`
`30
`
`USE OF RAPAMYCIN IN TREATMENT OF
`TUMORS
`This a continuation-in-part application of co-pending 5
`application Ser. No. 07/682,813, filed Apr. 9, 1991 and
`now U.S. Pat. No. 5,066,493, which in turn is a con
`tinuation-in-part application of co-pending application
`Ser. No. 07/391,334, filed Aug. 9, 1989 and now aban
`doned, which in turn is a divisional application of co- 10
`pending application Ser. No. 06/592,193, filed on Mar.
`22, 1984, now issued as U.S. Pat. No. 4,885,171, on Dec.
`5, 1989, which in turn is a continuation application of
`co-pending application Ser. No. 06/126,276, filed on
`Mar. 3, 1980, now abandoned, which in turn is a contin- 15
`uation application of co-pending application Ser. No.
`05/957,626, filed Nov. 3, 1978, now abandoned.
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`This invention relates to the use of rapamycin as an
`anti-cancer or anti-tumor agent.
`2. Description of the Prior Art
`Rapamycin is an antifungal antibiotic described by C.
`Vezina et al., J. Antibiot., 28, 721 (1975), S. N. Sehgal et
`al., J. Antibiot., 28, 727 (1975) and S. N. Sehgal et al.,
`U.S. Pat. No. 3,929,992, issued Dec. 30, 1975, filed Apr.
`12, 1974. Rapamycin is extracted from a streptomycete
`(Streptomyces hygroscopicus) isolated from an Easter
`Island soil sample and is particularly effective against
`Candida albicans both in vitro and in vivo.
`In addition, a recent report by R. R. Martel et al.,
`Can. J. Physiol., 55, 48 (1977) describes the use of rapa
`mycin for the prevention of the development of two
`experimental immunopathies [(experimental allergic 35
`encephalomyelitis (EAE) and adjuvant arthritis (AA)].
`The latter report also describes the inhibitory effect of
`rapamycin on the formation of humoral (IgE-like) anti
`body. This report concludes that immunosuppressant
`activity of rapamycin appears to be related to inhibition 40
`of the lymphatic system.
`SUMMARY OF THE INVENTION
`According to this invention a method is provided for
`treating malignant neoplasms in a mammal which com- 45
`prises administering to said mammal an antineoplastic
`amount of rapamycin. More specifically, rapamycin
`inhibits the proliferation of malignant cells, controls the
`growth of malignant neoplasms, reduces the size of
`malignant neoplasms, eradicates malignant neoplasms, 50
`prolongs the survival time of said mammal, kills malig
`nant cells, and adversely affects malignant cells.
`DETAILS OF THE INVENTION
`According to the present method, rapamycin is em
`55
`ployed as the active agent. The isolation and description
`of rapamycin is given in U.S. Pat. No. 3,929,992, cited
`above, herein incorporated by reference.
`Rapamycin is administered, either orally or parenter
`ally, to a carcinogenic tumor bearing mammal for the 60
`purpose of inhibiting the proliferation of malignant
`cells, controling the growth of malignant neoplasms,
`reducing the size of malignant neoplasms, eradicating
`malignant neoplasms, prolonging the survival time of
`said mammal, killing malignant cells, and adversely 65
`affecting malignant cells.
`While rapamycin can be administered above, e.g. as a
`sole component of a filled capsule, it is preferred to
`
`5,206,018
`2
`formulate the compound in various dosage forms for
`oral or parenteral administration, e.g. tablets or sterile
`solutions. Such formulations are described in U.S. Pat.
`No. 3,929,992, cited above. Rapamycin may also be
`administered in combination with a therapeutically ef
`fective amount of an antineoplastic agent commonly
`used in cancer therapy.
`When the antifungal antibiotic of this invention is
`employed as an anticancer agent in warm-blooded ani
`mals, e.g. rats, it may be used alone or in combination
`with a therapeutically effective amount of an antineo
`plastic agent commonly used in cancer therapy and
`with pharmaceutically acceptable carriers, the propor
`tion of which is determined by the solubility and chemi
`cal nature of the compounds, chosen route of adminis
`tration and standard biological practice. For example,
`an antineoplastic effective amount of the antibiotic may
`be administered alone or in combination orally in solid
`form containing such excipients as starch, sugar, certain
`types of clay and so forth. Similarly, such an amount
`may also be administered orally in the form of solutions
`or suspensions, or the antibiotic may be injected paren
`terally alone or in combination. For parenteral adminis
`tration the antibiotic may be used alone or in combina
`tion in the form of a sterile solution or suspension con
`taining other solutes or suspending agents, for example,
`enough saline or glucose to make the solution isotonic,
`bile salts, acacia, gelatin, sorbitan monooleate, polysor
`bate 80 (oleate esters of sorbitol and its anhydrides co
`polymerized with ethylene oxide) and the like.
`When utilizing rapamycin alone or in combination
`with a therapeutically effective amount of an antineo
`plastic agent commonly used in cancer therapy for the
`treatment of tumors, the total dose of active agent can
`range from 0.01 to 250 mg per kg of body weight per
`day with a preferred dosage range from 0.1 to 50 mg per
`kg of body weight per day. However, as the dosage of
`rapamycin to be administered by the method of this
`invention will of course vary with the tumor or cancer
`and tolerance of the mammal, and with the nature of the
`other antineoplastic agents used in combination. The
`schedule of dosing can range from one to five times per
`day to a single dose given every two to ten days. In
`creasing the frequency of administration is expected to
`reduce the amount of active drug needed per dose. Such
`dosages and scheduling of administration must be deter
`mined on an individual basis, depending upon the tumor
`or cancer, nutritional state of the mammal, age of the
`mammal, toxicity in each individual, and with the na
`ture of the other antineoplastic agents used in combina
`tion, etc.
`Rapamycin was evaluated in several National Cancer
`Institute standard tumor test procedures. The results
`showed that rapamycin reduces tumor size in and pro
`longs the survival time of tumor-bearing mammals.
`More specifically, rapamycin is useful for controlling
`the following carcinogenic tumors in standard mamma
`lian tumor models: lymphatic leukemia, colon, mam
`mary, melanocarcinoma and ependymoblastoma. The
`effectiveness of rapamycin in this respect was demon
`strated in the laboratory with rodents having trans
`planted tumors. Details of methods used to evaluate this
`effect are described in various publications; for exam
`ple, R. I. Geran et al., Cancer Chemother. Rep., Part 3,
`3, (No. 2) 1–103 (1972) and references therein. In addi
`tion, the protocols for the antitumor tests are available
`from the National Cancer Institute, Bethesda, Md., .
`U.S.A. These models have been adopted by the Na
`
`Ex. 1063-0002
`
`

`
`5,206,018
`3
`tional Cancer Institute as standard test procedures for
`predicting clinical activity of new chemotherapeutic
`agents.
`Tables 1 to 6 show the effects of therapy with rapa
`mycin on various tumors or cancers in rodents. More 5
`specifically, Table 1 shows the prolongation of survival
`time of female CDF1 mice implanted with lymphatic
`leukemia P388 by administering rapamycin; Table 2
`shows the reduction in size of colon 38 tumors in female
`BDF1 mice by administering rapamycin; Table 3 shows
`the prolongation of survival time of male CDF1 mice
`implanted with colon 26 tumors by administering rapa
`mycin; Table 4 shows the reduction in size of CD8Fl
`mammary tumors in male CD8F1 rats by administering
`15
`rapamycin; Table 5 shows the prolongation of survival
`time of female BDF1 mice implanted with B16 melono
`carcinoma by administering rapamycin; and Table 6
`shows the prolongation of survival time of male Swiss
`mice implanted with ependymoblastoma by administer- 20
`ing rapamycin.
`
`4
`TABLE 3-continued
`Effect of Rapamycin on Survival Time of CDF1 Mice
`Implanted with Colon 26 Tumor
`Dose/ Ave. Wt. Difference
`MST
`Inj.
`of Animals
`days
`Survivors
`mg/kg
`(T-C, g)
`on Day 5 T C
`12.5
`0.3
`10/10
`30.4
`19.1
`Treatment:
`Single intraperitoneal injection on days 1, 5 and 9 in a vehicle of saline with Tween
`$0.
`Evaluation:
`T/C96 = Median survival time (MST) in days of treated animals (T)/control
`animals (C) x 100. A T/C9% of 125 or greater is considered as a significant prolon
`gation of host survival. Evaluation done on day 60.
`
`T/Cº.,
`MST
`159
`
`10
`
`TABLE 4
`Effect of Rapamycin on CD8Fl
`M
`Tumors in CD8F1 Rats
`Average
`Dose/ Net Wt, Difference
`Inj.
`of Animals
`mg/kg
`(T-C, g)
`400
`–6.6
`200
`–6.5
`100
`–4.8
`50
`–4. I
`25
`–2.4
`12.5
`–0.8
`Treatment:
`Single intraperitoneal injection on days 1, 8, 15, 22 and 29 in a vehicle of saline with
`Tween-80.
`Evaluation:
`T/C} = Median tumor weight (MTW) estimated from tumor diameter of treated
`animals (T)/control animals (C) × 100. A TACº of 42 or less is considered as a
`significant inhibitor of tumor growth. Evaluation done on day 30.
`
`MTW
`T/C9%
`days
`Survivors
`on Day 5 T C MTW
`4/10
`0 3200
`-
`10/10
`323 3200
`10
`10/10
`448 3200
`14
`10/10
`755 3200
`23
`10/10
`825 3200
`25
`10/10
`928 3200
`29
`
`TABLE 5
`Effect of Rapamycin on B16 Melanocarcinoma in BDF, Mice
`Average
`Dose/ Net Wt. Difference
`Inj.
`of Animals
`mg/kg
`(T-C, g)
`400
`–3.3
`200
`— 1.5
`100
`— 1.2
`50
`–0.7
`25
`0.1
`12.5
`0.1
`Treatment:
`Single intraperitoneal injection on each of days l through 9 in a vehicle of saline
`with Tween-80,
`Evaluation:
`T/C} = Median Survival Time (MST) in days of treated animals (T) control
`animals (C) × 100. A TAC9% of 125 or greater is considered as a significant prolon
`gation of host survival. Evaluation done on day 60.
`
`MST
`days
`Survivors
`on Day 5 T C
`10/10
`22.0 20.1
`10/10
`22.3
`20.1
`10/10
`28.0 20, 1
`10/10
`25.3 20, 1
`10/10
`28.0 20.1
`10/10
`29.0 20.1
`
`T/C9%
`MST
`109
`110
`139
`125
`139
`144
`
`TABLE 6
`Effect of Rapamycin on Ependymoblastoma in Swiss Mice
`Average
`Dose/ Net W?. Difference
`Inj.
`of Animals
`mg/kg
`(T-C, g)
`200
`—3.3
`100
`–2.2
`50
`— 1.3
`25
`–2.0
`12.5
`— 1.0
`Treatment;
`Single intraperitoneal injection on each of days 1 through 9 in a vehicle of saline
`with Tween-80,
`Evaluation:
`T/C} = Median Survival Time (MST) in days of treated animals (T) control
`animals (C) × 100. A TVCº. of 125 or greater is considered as a significant prolon
`gation of host survival. Evaluation done on day 60.
`
`MST
`days
`Survivors
`on Day 5 T C
`10/10
`44.0 18.1
`10/10
`26.0 18.1
`9/10
`34.0 18.1
`10/10
`34.0 18.1
`10/10
`32.3
`18.1
`
`T/Cº.
`MST
`243
`143
`187
`187
`178
`
`TABLE 1
`Effect of Rapamycin on Survival Time of CDF1 Mice
`Implanted with Lymphatic Leukemia P-388 (ascetic)
`Dose/ Ave. Wt. Difference
`MST
`Inj.
`of Animals
`days
`mg/kg
`(T-C, g)
`T C
`400
`— 1.9
`14.1
`10.2
`200
`–2.4
`f3.1
`10.2
`100
`— 1.6
`13.7
`10.2
`50
`– 1.9
`j4.3
`10.2
`25
`— 1.6
`13.9
`#0.2
`12.5
`–0.6
`13.9
`10.2
`Treatment:
`Nine intraperitoneal injections starting on day one in a vehicle of saline with
`Tween-80 [Trade Mark for a derivative of Z-sorbitan mono-9-octadecenoate poly- 35
`(oxy-1,2-ethanediyl)].
`Evaluation:
`T/Cº = Median Survival Time (MST) in days of treated animals (T)/control
`animals (C) × 100. A T/C} of 125 or greater is considered as a significant prolon
`gation of host survival. Evaluation done on day 30.
`
`25
`
`30
`
`T/Cº.,
`MST
`138
`128
`134
`140
`136
`136
`
`Survivors
`on Day 5
`6/6
`6/6
`6/6
`6/6
`6/6
`6/6
`
`40
`
`TABLE 2
`Effect of Rapamycin on Colon 38 Tumor Weight in Mice
`Dose/ Ave. Wt. Difference
`MTW
`T/Cº.,
`Inj.
`of Animals
`Ing
`mg/kg
`(T-C, g)
`T C MTW 45
`400
`–3.4
`188
`810
`23
`200
`—2.0
`209 810
`25
`100
`–0.8
`272
`810
`33
`50
`–0.8
`320 810
`39
`25
`–0.4
`368
`810
`45
`12.5
`0.4
`368
`810
`45
`Treatment:
`Single intraperitoneal injection on days 2, 9 and 16 in a vehicle of saline with Tween
`80.
`Evaluation:
`T/C} = Median tumor weight (MTW) estimated from tumor diameter of treated 55
`animals (T)/control animals (C) × 100. A TAC3% of 42 or less is considered as a
`significant inhibitor of tumor growth. Evaluation done on day 20.
`
`Survivors
`on Day 5
`10/10
`10/10
`10/10
`9/10
`10/10
`10/10
`
`50
`
`TABLE 3
`Effect of Rapamycin on Survival Time of CDF1 Mice
`Implanted with Colon 26 Tumor
`Dose/ Ave. Wt. Difference
`MST
`Inj.
`of Animals
`days
`Survivors
`mg/kg
`(T-C, g)
`on Day 5 T C
`400
`–2,4
`10/10
`26.3
`19.1
`200
`— 1.8
`10/10
`25.8
`19.1
`100
`— 1.4
`10/10
`29.0 19.1
`50
`–0.8
`10/10
`30.6 19.1
`25
`–0.3
`10/10
`30.3
`19.1
`
`T/Cº.,
`MST
`137
`135
`151
`160
`158
`
`65
`
`Ex. 1063-0003
`
`

`
`10
`
`15
`
`20
`
`5,206,018
`5
`6
`untreated control group). At all doses tested, rapamycin
`The standard animal models used can be divided into
`two types based on how the results are expressed. Re
`caused a significant increase in survival time of the host
`Sults can be expressed as a comparison of the median
`mammal in the ependymoblastoma standard test proce
`survival time for mammals in the treated (T) group
`dure, and is therefore useful in treating malignant cen
`(those treated with rapamycin) versus the median sur
`tral nervous system neoplasms. The extremely favor
`vival time for mammals in the untreated control (C)
`able results obtained in this test procedure also indicate
`group. The result is given as a percentage of T/C; a
`that rapamycin is capable of reaching the intracranial .
`high percent T/C indicates that the compound that was
`neoplasm by crossing the blood brain barrier. Malignant
`tested was effective in treating the malignant neoplasm
`central nervous system neoplasms describes a broad
`that was evaluated. Statistically significant results are
`class of intracranial neoplasms which include, but are
`observed at either 125 or 130% T/C, depending on the
`not limited to: intracranial meningiomas, sarcomas,
`neoplasm that was evaluated. Alternatively, the results
`gliomas, astrocytomas, medulloblastomas, schwan
`of certain tests for solid tumors can be expressed based
`nomas, ependymomas, meningiomas, germinomas, and
`on the tumor weight of the solid tumor after the evalua
`the like.
`tion period. The tumor weight in the test (T) animals is
`Rapamycin was weakly active in the P-388 leukemia
`compared with the tumor in the control (C) animals and
`standard test procedure; a maximal % T/C of 140 was
`the results are expressed as a percent T/C. When results
`achieved at a dose of 50 mg/kg. When comparing these
`are expressed as a function of tumor weight, a low %
`data to other data obtained for other anti-leukemic com
`T/C indicates effective treatment of the neoplasm, as
`pounds described in the literature, rapamycin is not felt
`the tumors in the test animals are smaller than tumors in
`to be useful in treating higher mammalian leukemias.
`the untreated control animals. A percent T/C of less
`Rapamycin also can be used to produce beneficial
`than 42 is considered to be statistically significant.
`effects in the treatment of malignant neoplasms when
`The results of the above described National Cancer
`combined with a therapeutically effective amount of an
`Institute standard tumor test procedures demonstrate
`antineoplastic agent commonly used in cancer therapy.
`rapamycin's antineoplastic activity in mammals. As
`25
`Such antineoplastic agents include the alkylating
`such rapamycin is useful in treating malignant neo
`agents, for example, busulfan, chlorambucil, cyclophos
`plasms. Treating broadly includes, but is not limited to,
`phamide, mechlorethamine hydrochloride, melphalan,
`inhibiting the proliferation of malignant cells, control
`pipobroman, thiotepa and uracil mustard; antimetabo
`ling the growth of malignant neoplasms, reducing the
`lites, for example, cytarabine, fluorouracil, floxuridine,
`size of malignant neoplasms, eradicating malignant neo
`30
`mercaptopurine, methotrexate and thioguanine; miscel
`plasms, prolonging the survival time of said mammal,
`laneous anticancer agents, for example, dacarbazine,
`killing malignant cells, and adversely affecting malig
`hydroxyurea, mitotane, procarbazine hydrochloride,
`nant cells. Preferred embodiments of this invention, that
`quinacrine hydrochloride, vinblastine sulfate and vin
`are described below, are based on the specific types of
`cristine sulfate; estogens, for example, chlorotrianisene,
`malignant neoplasms that rapamycin has been shown to
`35
`conjugate estogens (e.g. PREMARIN (8), diethylstil
`be effective in treating. The scope of this invention,
`bestrol and the like; androgens, for example, methyltes
`however, is not limited to these specific embodiments,
`tosterone, testosterone and the like; adrenal corticoster
`as other neoplasms that rapamycin is effective in treat
`oids, for example, prednisone and the like; progesta
`ing will be apparent to one skilled in the art.
`gens, for example, megestrol, hydroxyprogesterone
`Based on the ability of rapamycin to significantly
`caproate and the like; radioactive isotopes; and antibiot
`inhibit tumor growth in the Colon 38 standard test pro
`ics, for example, bleomycin sulfate, doxorubicin hydro
`cedure, as seen by a reduction in tumor size, and in
`chloride and the like. Suitable methods of administra
`crease survival time of the host mammal in the Colon 26
`tion, compositions and dosages of the antineoplastic
`standard test procedure, rapamycin is useful in treating
`agents are described in medical textbooks; for instance,
`mammalian carcinomas of the colon and rectum. The
`45
`“PHYSICIANS’ DESK REFERENCE”, 32nd ed.,
`use of rapamycin in treating colon cancer is covered in
`Medical Economics Co., Oradell, N.J. U.S.A., 1978 and
`U.S. Pat. No. 4,885,171.
`“AMA DRUG EVALUATIONS”, 3rd ed. PSG Pub
`In the CD8F1 mammary tumor test procedure, rapa
`lishing Company, Inc., Littleton, Mass., U.S.A. pp
`mycin caused a reduction in tumor size at doses of up to
`1106–1151, 1977. When used in combination, rapamycin
`200 mg/kg. Mammary tumors were reduced in weight
`is administered as described previously; however, a
`by 71% at 12.5 mg/kg and by 90% at a dose of 200
`lower dose can be used for efficacious results.
`mg/kg, indicating an almost complete eradication of the
`mammary carcinoma. As such, rapamycin is useful in
`We claim:
`-
`1. A method of treating a malignant neoplasm se
`treating mammalian breast neoplasms.
`lected from the group consisting of a mammary carci
`A significant increase in survival time of the host
`noma, a skin carcinoma, and a central nervous system
`mammal was observed in the B16 melanocarcinoma
`neoplasm in a mammal in need thereof which comprises .
`standard test procedure for mice that were treated with
`administering an antineoplastic amount of rapamycin to
`doses of up to 100 mg/kg. As such, rapamycin is useful
`said mammal orally or parenterally with the proviso
`in treating skin carcinomas such as basal cell carcinoma,
`that said malignant neoplasm has not been transplanted
`squamous cell carcinoma, malignant melanoma, and the
`into said mammal.
`like.
`2. The method of claim 1 wherein the skin carcinoma
`The ependymoblastoma standard test procedure is
`is selected from the group consisting of a basal cell
`predictive of a compound's ability to treat malignant
`carcinoma, squamous cell carcinomas, and malignant
`central nervous system neoplasms. At a dose of 50
`melanoma.
`mg/kg, a 7% T/C of 187 was obtained, and at a dose of
`65
`3. The method of claim 1 wherein the central nervous
`200 mg/kg, a % T/C of 243 was obtained (median
`system neoplasm is an intracranial neoplasm selected
`survival time of 44.0 days for mammals treated with
`from the group consisting of a meningioma, sarcoma,
`rapamycin versus median survival time of 18.1 days for
`
`60
`
`50
`
`55
`
`Ex. 1063-0004
`
`

`
`5,206,018
`8
`7
`glioma, astrocytoma, medulloblastoma, schwannoma,
`8. The method of claim 7 wherein the skin carcinoma
`ependymoma, meningioma, and germinoma.
`is selected from the group consisting of a basal cell
`4. A method of inhibiting the proliferation of malig
`carcinoma, squameous cell carcinomas, and malignant
`nant cells selected from the group consisting of a mam
`melanoma.
`mary carcinoma, a skin carcinoma, and a central ner
`9. The method of claim 7 wherein the central nervous
`5
`system neoplasm is an intracranial neoplasm selected
`vous system neoplasm in a mammal in need thereof
`which comprises administering an antineoplastic
`from the group consisting of a meningioma, sarcoma,
`amount of rapamycin to said mammal orally or paren
`glioma, astrocytoma, medulloblastoma, schwannoma,
`ependymoma, meningioma, and germinoma.
`terally with the proviso that said malignant cells have
`10. A method of eradicating a malignant neoplasm
`not been transplanted into said mammal.
`selected from the group consisting of a mammary carci
`5. The method of claim 4 wherein the skin carcinoma
`is selected from the group consisting of a basal cell
`noma, a skin carcinoma, and a central nervous system
`neoplasm in a mammal in need thereof which comprises
`carcinoma, squameous cell carcinomas, and malignant
`administering an antineoplastic amount of rapamycin to
`melanoma.
`said mammal orally or parenterally with the proviso
`6. The method of claim 4 wherein the central nervous
`that said malignant neoplasm has not been transplanted
`system neoplasm is an intracranial neoplasm selected
`from the group consisting of a meningioma, sarcoma,
`into said mammal.
`glioma, astrocytoma, medulloblastoma, schwannoma,
`11. The method of claim 10 wherein the skin carci
`ependymoma, meningioma, and germinoma.
`noma is selected from the group consisting of a basal
`cell carcinoma, squameous cell carcinomas, and malig
`7. A method of reducing the size of a malignant neo
`20
`plasm selected from the group consisting of a mammary
`nant melanoma.
`12. The method of claim 10 wherein the central ner
`carcinoma, a skin carcinoma, and a central nervous
`vous system neoplasm is an intracranial neoplasm se
`system neoplasm in a mammal in need thereof which
`comprises administering an antineoplastic amount of
`lected from the group consisting of a meningioma, sar
`rapamycin to said mammal orally or parenterally with
`coma, glioma, astrocytoma, medulloblastoma, Schwan
`25
`noma, ependymoma, meningioma, and germinoma.
`the proviso that said malignant neoplasm has not been
`transplanted into said mammal.
`
`#.
`
`sº
`
`* 2. *
`
`10
`
`15
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`Ex. 1063-0005