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`POINT SUR...
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`© John Libbey Eurotext
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`Rapamycin and CCI-779
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`Jérôme ALEXANDRE
`Eric RAYMOND
`Jean-Pierre ARMAND
`_________________________
`
`Medicine Department, Institut
`Gustave-Roussy, Villejuif Cedex
`94805.
`_____________________________
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`
`
`Abstract - Rapamycin (sirolirnus) is a macrolide related to cyclosporine with immuno-
`suppressive properties and antiproliferative activity in various human tumor cell lines and
`tumor xerograph models. The cytosolic kinase mTOR which controls the initiation of the
`translation of messenger RNA is the main known target of Rapamycin. During clinical
`studies, Rapamycin given by oral route as immunosuppressant did not show dose-limited
`toxicity and only asymptomatic thrombopenia and hyperlipemia were observed. In
`murine models, best antitumoral activity was observed using parental routes. CCI-779,
`an analog formulated for intravenous use has antitumor activity without significant
`immunosuppressive property in mice and is currently in Phase I trials in man.▲
`Key words: Rapamycin, mTOR, CCI-779.
`
`Article received on June 15, 1999,
`accepted after review on August 9,
`1999.
`Reprints: J. Alexander
`
`Rapamycin (Figure 1) or Sirolimus is a macrolide
`produced by Streptomyces hygroscopicus, similar to
`cyclosporine and FK506 (tacrolimus). It was initially
`identified as an antifungal agent thirty years ago. [1]
`Secondarily, it has mainly been developed as an
`immunosuppressant
`agent
`(Rapamune®, Wyeth-
`Léderlé). Several clinical trials have shown its value in
`the treatment of organ graft rejection [2]. Its anti-tumor
`properties in different cell models have also been known
`for several years, but have never been the subject of
`publications on human clinical trials [3]. The originality
`of rapamycin is its mechanism of action. It specifically
`inhibits a cytoplasmic protein kinase, mTOR (for
`mammalian Target Of Rapamycin) that is involved in a
`path of mitogenic signaling which regulates translation
`initiation [4].
`Interest in rapamycin was recently revived with the
`development of analogs, such as CCI-779 (Figure 1),
`
`
`
`
`
`808
`
`showing, in preclinical models, an antiproliferative
`activity and a weak immunosuppressive effect [5].
`
`
`
`Rapamycin
`
`CCI-779
`
`Figure 1. Rapamycin and CCI-779
`
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`Rapamycin and CCI-779
`
`Rapamycin
`Antitumoral activity
`
`In vitro, rapamycin inhibits the growth of several human tumor
`cell lines, especially osteosarcoma [6], Rh1 and Rh30
`rhabdomyosarcoma [7], of H69, H345 and H510 small cell
`lung cancers [8], of H4 hepatoma [9] and of hormone-
`dependent MCF7 breast cancer [10]. The range of effective
`concentrations is from 0.3 to 50 nM. In many of these lines, it
`has been shown that rapamycin blocks the cells in the G1 phase
`of the cell cycle. This cytostatic effect was confirmed in vivo
`in human tumor xenograft models in nude mice. [3] A
`proapoptotic effect was also observed on rhabdomyosarcoma
`lines grown without growth factor [11] and in combination
`with cisplatin on an ovarian carcinoma cell line [12].
`
`Mechanisms of molecular action
`Rapamycin can be considered a ''prodrug'' insofar as its
`intracellular action requires attachment to an immunophilin
`called FKBP12 (FK506 binding protein because it also
`attaches FK506) [13]. The complex thus formed is very stable
`(duration of half-dissociation is 17.5 h) and allows a prolonged
`biological effect of rapamycin (7 days after one hour of
`exposure in vitro) [11], suggesting that the latter may be
`administered intermittently.
`The only currently known target of the rapamycin/FKBP12
`complex is mTOR. It is a serine/threonine kinase of the
`phosphatidylinositol kinases family [4]. It is activated by a
`large number of growth factors, in particular interleukins 2, 4
`and 6, insulin, and insulin-like growth factor 1. In response to
`these mitogenic stimuli, mTOR activates the initiation of the
`translation of many mRNAs by two parallel pathways [4, 14]
`(Figure 2):
`- Initiation factor 4E of the translation (eIF4E) is in the basal
`state sequestered and inhibited by the 4E-BP1 protein. mTOR,
`by phosphorylating the latter, will allow the release of eIF4E
`and the initiation of the translation. The thus synthesized
`proteins are assumed to induce, directly or indirectly, the G1/S
`transition;
`- mTOR activates the p70/S6 kinase which itself then activates
`the ribosomal protein S6. In its phosphorylated form, the latter
`selectively controls the translation of mRNAs having a
`pyrimidine-rich domain at their 5' end. These mRNAs encode
`ribosomal proteins and elongation factors.
`Protein activated factors upstream of mTOR after binding of
`the growth factor to its receptor are less known. An isoform of
`p85/PI kinase may, particularly, be involved [15].
`The inhibition of the biological function of mTOR by
`rapamycin appears to play a key role in its cytostatic action.
`However, there is still much to learn on, firstly, the exact
`mechanisms by which mTOR controls the G1/S transition and,
`secondly, on any other cellular targets of rapamycin. Thus, it
`has recently been shown in 3T3 mouse fibroblasts stimulated
`with serum that rapamycin decreased the cyclin DI rate.
`However, unlike what one might believe, this was not due to a
`defective synthesis but to an accelerated degradation of the
`protein [16]. On other models, rapamycin induces
`
`Initiation of the translation
`
`
`
`
` Transduction pathway involving mTOR. Fc:
`Figure 2.
`growth factor; Pl, Kase: phosphatidylinositol 3 kinase; mTOR:
`mammalian target of rapamycin; rapa: rapamycin; FKBP:
`FK506 binding protein; p70/S6Kase: ribosomal protein S6
`kinase; eIF4E: eukaryotic initiation factor 4E; 4E-BPI: eIF4E
`binding protein.
`accumulation of the cyclin inhibitor p27klp1 [17]. The
`proapoptotic action of rapamycin is also unclear. It seems
`dependent on mTOR inhibition, but not p53 [11], or bcl-2 [18].
`A better understanding of the mechanisms of action of
`rapamycin at the molecular level would ideally predict tumor
`sensitivity to this molecule as a function of the expression or
`non-expression of a particular gene. It has already been shown
`that tumors overexpressing c-myc were resistant to rapamycin
`[19], as well as those from patients with ataxia telangiectasia
`[20]. Interestingly, the ATM gene, deficient in the ataxia
`telangiectasia, encodes a phosphatidylinositol kinase close to
`mTOR.
`
`Clinical experience
`It concerns mainly the use of rapamycin as immunosuppressant
`agent, alone or in combination with ciclosporin. Rapamycin is
`
`Bull Cancer 1999; 86 (10):808-11
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`809
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`J. Alexandre et al.
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`properties allow for easy intravenous administration.
`CCI-779 is one of these analogs. It has a cytostatic activity on
`several xenograft models of human tumors in nude mice,
`particularly in glioblastoma, prostate, pancreatic and breast
`carcinoma [23] and medulloblastoma [24].
`Like rapamycin, attaching the CCI-779 to the FKBP12 is an
`essential step in its action [23]. It remains to determine whether
`it is possible to completely superimpose CCI-779's mechanism
`of action on that of rapamycin.
`Interestingly, the antitumor activity described in nude mice is
`kept for 14 days after a daily administration over 5 days while
`the immunosuppressive effect disappears after 24 h [23].
`Phase I clinical trials are underway in France and the United
`States.
`
`Conclusion
`Rapamycin is the first representative of a new class of
`anticancer agents with a completely original mechanism of
`action and a favorable toxicity profile. Preclinical studies
`suggest that those molecules have an essentially cytostatic
`action. CCI-779, first analog administered parenterally, is
`currently the subject of Phase I clinical trials. In parallel, better
`knowledge of the molecular targets of rapamycin and its
`analogs could guide the achievement of future Phase II clinical
`trials.▼
`
`
`
`9. Price DJ, Grove JR, Calvo V, Avruch J, Bierer BE.
`Rapamycin-induced inhibition of the 70-kilodalton 56 protein
`kinase. Science 1992; 257: 973-7.
`10. Magge KP, Pryor AD, Marks JR, Iglehart JD, Miron A.
`Rapamycin (sirolimus) blocks estrogen mediated growth of
`breast cancer cell lines. Proc Am Ass Cancer Res 1999; 40: 636
`(abstr. 4197).
`11. Hosoi H, Dilling MB, Shikata T, Lia LN, Shu L, Ashmun
`RA. Rapamycin causes poorly reversible inhibition of mTOR
`and
`induces
`p53-dependent
`apoptosis
`in
`human
`rhabdomyosarcoma cells. Cancer Res 1999; 59: 886-94.
`12. Shi Y, Frankel A, Radvanyi LG, Penn LZ, Miller RG,
`Mills GB. Rapamycin enhances apoptosis and increases
`sensitivity to cisplatin in vitro. Cancer Res 1995; 55: 1982-8.
`13. Sabers CJ, Martin MM, Brunn GJ. Isolation of a protein
`target of the FKBP12-rapamycin complex in mammalian cells.
`J Biol Chem 1995; 270: 815-22,
`14. Beretta L, Grolleau A. La rapamycine; identification
`d’une nouvelle voie de signalisation des facteurs de croissance,
`réglant le début de la traduction. 1998; 14: 600-2.
`15. Conus NM, Hemmings BA, Pearson RB. Differential
`regulation by calcium reveals distinct signaling requirements
`for the activation of Akt and p705GK. J Biol Chem 1998; 273:
`4776-82.
`16. Hashemolhosseini S, Nagamine Y, Morley SJ,
`Desrivieres S, Mercep L, Ferrari S. Rapamycin inhibition of
`the Gl to S transition is mediated by effects on cyclin Dl mRNA
`and protein stability. J Biol Chem 1998; 273; 14424-9.
`
`administered orally and is metabolized by cytochrome P450
`3A in several inactive metabolites [21]
`At the recommended dose for Phase II of 7 mg/m2/day, toxicity
`mainly involves biological parameters [2]. There is a dose-
`dependent haematological toxicity predominant on platelets,
`and usually asymptomatic and not requiring transfusion. This
`haematotoxicity is of central origin and may be related to
`inhibition by rapamycin of mitogenic signals from the
`cytokines. Rapamycin increases the levels of triglycerides and
`cholesterol sometimes considerably. This hyperlipemia could
`be especially problematic when administered long-term due to
`the increased cardiovascular risk. No acute pancreatitis or other
`clinical manifestation associated with hypertriglyceridemia
`severely
`those already
`was ever observed. Among
`immunocompromised patients, rapamycin does not appear to
`increase the risk of infections, except perhaps those related to
`herpes simplex virus. This finding should be linked to the fact
`that rapamycin increases the translation of mRNAs of certain
`viruses [22].
`
` A
`
` new analog of rapamycin: CCI-779
`In several mouse models, the antitumor action of rapamycin is
`most important when parenteral administration is used.
`However, it is difficult to achieve in routine clinical practice
`due to a low solubility of the molecule [5]. Thus analogues of
`rapamycin have been developed whose physicochemical
`
`REFERENCES
`________________________________________________________
`1. Vezina C. Antimicrobial activity of streptomyces and
`fungi isolated from rapa Nui soil samples. 5th annual meeting
`of the Canadian Society of Chemotherapy, Toronto, April 16,
`1969.
`2. Kahan BD. Rapamycin: personal algorithms for use based
`on 250 treated renal allograft recipients. Transplant Proc 1998;
`30: 2185-8.
`3. Morris RE. Rapamycins:
`antitumor,
`antifungal,
`antiproliferative,
`and
`immunosuppressive molecules.
`Transplant Rev 1992; 6: 39-87.
`4. Thomas G, Hall MN. TOR signaling and. control of cell
`growth. Curr Op Cell Biol 1997; 9:782-7.
`5. Sausville
`EA.
`New
`agents-noncytotoxics,
`antiangiogenesis. ASCO Educational Book 1998; 112-7.
`6. Albers MW, Williams RT, Brown EJ, Tanaka A, Hall FL,
`Schreiber SL ,FKBP-rapamycin inhibits a cyclin-dependent
`kinase activity and a cyclin Dl-cdk association in early G1 of
`an osteosarcoma cell line. J Biol Chem 1993; 268; 22825-9.
`7. Dilling MB, Dias P. Shapiro DN, Germain GS, Johnson
`RK, Houghton PJ. Rapamycin selectively inhibits the growth
`of childhood rhabdomyosarcoma cells through inhibition of
`signaling via the type 1 insulin-like growth factor receptor.
`Cancer Res 1994; 54: 903-7.
`8. Seufferlein T, Rozengurt E. Rapamycin
`inhibits
`constitutive p70S6K phosphorylation, cell proliferation, and.
`colony formation in small cell lung cancer cells. Cancer Res
`1996; 56; 3895-7.
`
`810
`
`
`
`Bull Cancer 1999; 86 (10):808-11
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`17. Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee
`MH, et al Interleukin-2-mediated elimination of the p27kp1
`cyclin-dependent kinase inhibitor prevented by rapamycin.
`Nature 1994; 372: 570-3.
`18. Veverka KA, Germain GS, Dilling MB, Houghton PJ.
`Overexpression of bcl2 fails to protect rhabdomyosarcoma
`cells from rapamycin-induced apoptosis. Proc Am Ass Cancer
`Res 1998; 39: 571 (abstr. 3880).
`19. Dilling MB, Hosoi H, Liu LN, Germain GS, Houghton
`PJ. Intrinsic resistance to rapamycin in human tumor cells may
`correlate with c-myc protein levels. Proc Am Ass Cancer Res
`1999; 40: 428 (abstr. 2827).
`20. Beamish H, Williams R, Chen P, Khanna KK, Hobson K,
`Watters D. Rapamycin resistance in ataxia-telangiectasia.
`Oncogene 1996; 13: 963-70.
`21. Trépanier DJ, Gallant H, Legatt DF, Yatscoff RW.
`
`Bull Cancer 1999; 86 (10):808-11
`
`
`
`
`
`
`Rapamycin and CCI-779
`
`Rapamycin : distribution, pharmacokinetics and therapeutic
`range investigations: an update. Clin Biochem 1998; 31: 345-
`51.
`22. Beretta L, Svitkin YV, Sonenberg N. Rapamycin
`stimulates viral protein synthesis and augments the shutoff of
`host protein synthesis upon picornavirus infection. J Virol
`1996; 70: 8993-6.
`23. Gibbons JJ, Discafani C, Peterson R, Hernandez R,
`Skotnicki J, Frost P. The effect of CCI-779, a novel macrolide
`anti-tumor agent, on the growth of human tumor cells in vitro
`and in nude mouse xenografts in vivo, Proc Am Ass Cancer
`Res 1999 ; 40: 301 (abstr. 2000).
`24. Geoerger B, Kerr K, Janss AJ, Sutton LN, Phillips PC.
`Rapamycin analog CCI-779 inhibits growth of human
`medulloblastoma xenografts. Proc Am Ass Cancer Res 1999;
`40; 603 (abstr. 3978),
`
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`
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`November 2, 2016
`
`Certification
`
`Park IP Translations
`
`
`TRANSLATOR'S DECLARATION:
`
`I, Claudine Joly-King, hereby declare:
`
`That I possess advanced knowledge of the French and English languages. The
`attached French into English translation has been translated by me and to the
`best of my knowledge and belief, it is a true and accurate translation of the
`article entitled “La rapamycine et le CCI-779” in French and “Rapamycin and
`CCI-779” in English.
`
`
`________________________________________
`
`Claudine Joly-King
`
`Project Number: FCHS_1610_027
`
`
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`
`
`
`
` 15 W. 37th Street 8th Floor
`New York, NY 10018
`212.581.8870
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`j. Alexandre eta!.
`
`avec Ia ciclosporine. La rapamycine est administree par
`voie orale et est metabolisee par le cytochrome P450 3A en
`plusieurs metabolites inactifs [21 ].
`A Ia dose recommandee pour les phases II de 7 mglm 2/j, Ia
`toxicite porte essentiellement sur des parametres biologiques
`[2]. II existe une toxicite hematologique dose-dependante
`predominante sur les plaquettes, et generalement asympto(cid:173)
`matique et ne necessitant pas de transfusion. Cette hemato(cid:173)
`toxicite est d'origine centrale et pourrait etre liee a !'inhibition
`par Ia rapamycine des signaux mitogenes transmis par les
`cytokines. La rapamycine augmente le taux de triglycerides et
`de cholesterol parfois de fa<;on considerable. Cette hyperlipe(cid:173)
`mie pourrait surtout poser des problemes lors d'une adminis(cid:173)
`tration au long cours du fait de !'augmentation du risque car(cid:173)
`diovasculaire. II n'a jamais ete observe de pancreatite aigue
`liee a l'hypertriglyceridemie, ni d'autre manifestation cli(cid:173)
`nique. Chez ces patients deja lourdement immunodeprimes,
`Ia rapamycine ne semble pas augmenter le risque d'infec(cid:173)
`tions, sauf peut-etre celles liees au virus herpes simplex. Cette
`constatation est a rapprocher du fait que Ia rapamycine aug(cid:173)
`mente Ia traduction des ARI\Jm de certains virus [22].
`
`Un nouvel analogue de Ia rapamycine:
`le CCI-779
`
`Dans plusieurs modeles murins, !'action antitumorale de Ia
`rapamycine est plus importante lorsqu'une administration
`parenterale est utilisee. Cependant, celle-ci est difficilement
`realisable en pratique clinique courante du fait d'une faible
`solubilite de Ia molecule [5]. Des analogues de Ia rapamy(cid:173)
`cine ont done ete developpes dont les proprietes physico-
`
`chimiques permettent une administration par voie intravei(cid:173)
`neuse aisee.
`Le CCI-779 est l'un de ces analogues. II presente une acti(cid:173)
`vite cytostatique sur plusieurs modeles de xenogreffes de
`tumeurs humaines a des souris nude, en particulier dans des
`glioblastomes, carcinomes de prostate, du pancreas et du
`sein [23] et des medulloblastomes [24].
`Tout comme Ia rapamycine, Ia fixation du CCI-779 a Ia
`FKBP12 est une etape indispensable a son action [23]. II reste
`cependant a determiner si le mecanisme d'action du CCI-779
`est entierement superposable a celui de Ia rapamycine.
`De fa<;on interessante, l'activite antitumorale decrite chez Ia
`souris nude est maintenue pendant 14 jours apres une admi(cid:173)
`nistration quotidienne de 5 jours alors que l'effet immuno(cid:173)
`suppresseur disparalt au bout de 24 h [23].
`Des essais therapeutiques de phase I sont en cours en
`France et aux Etats-Unis.
`
`Conclusion
`
`La rapamycine est le premier representant d'une nou(cid:173)
`velle classe d'anticancereux au mecanisme d' action tout
`a fait original et au profil de toxicite favorable. Les
`etudes precliniques suggerent pour ces molecules une
`action essentiellement cytostatique. Le CCI-779, premier
`analogue administrable par voie parenterale, fait actuel(cid:173)
`lement I' objet d'essais cliniques de phase I. Parallele(cid:173)
`ment, une meilleure connaissance des cibles molecu(cid:173)
`laires de Ia rapamycine et de ses analogues pourrait
`guider Ia realisation de futurs essais cliniques de
`phase II. T
`
`REFERENCES
`
`1. Vezina C. Antimicrobial activicy of streptomyces and fungi isolated
`from rap a N ui soil sam pies. 5th annual meeting of the Canadian Society of
`Chemotherapy, Toronto, April 16, 1969.
`2. Kahan BD. Rapamycin: personal algorithms for use based on 250 trea(cid:173)
`ted renal allograft recipients. Transplant Proc 1998; 30: 2185-8.
`3. Morris RE. Rapamycins: antifungal, antitumor, anti proliferative, and
`immunosuppressive molecules. Transplant Rev 1992; 6: 39-87.
`4. Thomas G, Hall MN. TOR signalling and control of cell growth.
`Curr Op Cell Bioi 1997 ; 9 : 7 82-7.
`5. Sausville EA. New agents-noncytotoxics, antiangiogenesis. ASCO Edu(cid:173)
`cational Book 1998 : 112-7.
`6. Albers MW, Williams RT, Brown EJ, Tanaka A, Hall FL,
`Schreiber SL. FKBP-rapamycin inhibits a cyclin-dependent kinase activity
`and a cyclin 01-cdk association in early G1 of an osteosarcoma cell line.
`j Bioi Chern 1993; 268: 22825-9.
`7. Dilling MB, Dias P, Shapiro ON, Germain GS, Johnson RK, Hough(cid:173)
`ton PJ . Rapamycin selectively inhibits the growth of childhood rhabdo(cid:173)
`myosarcoma cells through inhibition of signaling via the type I insulin(cid:173)
`like growth factor receptor. Cancer Res 1994; 54: 903-7.
`8. Seufferlein T, Rozengurt E. Rapamycin inhibits constitutive p70S6K
`phosphorylation, cell proliferation, and colony formation in small ceU
`lung cancer cells. Cancer Res 1996; 56: 3895-7.
`
`9. Price OJ, Grove JR, Calvo V, Avruch J, Bierer BE. Rapamycin-indu(cid:173)
`ced inhibition of the 70-kilodalton 56 protein kinase. Science 1992; 257:
`973-7.
`10. Magge KP, Pryor AD, Marks JR, Iglehart JO, Miron A. Rapamycin
`(sirolimus) blocks estrogen mediated growth of breast cancer cell lines.
`Proc Am Ass Cancer Res 1999; 40: 636 (abstr. 4197).
`11. Hosoi H, Dilling MB, Shikata T, Liu LN, Shu L, Ashmun RA. Rapa(cid:173)
`mycin causes poorly reversible inhibition of mTOR and induces p53-
`dependent apoptosis in human rhabdomyosarcoma cells. Cancer Res
`1999; 59 : 886-94.
`12. Shi Y. Frankel A, Radvanyi LG, Penn LZ, Miller RG, Mills GB.
`Rapamycin enhances apoptosis and increases sensitivity to cisplatin in
`vitro. Cancer Res 1995 ; 55 : 1982-8.
`13. Sabers CJ, Martin MM , Brunn GJ . Isolation of a protein target of the
`FKBP 12-rapamycin complex in mammalian cells. J Bioi Chern 1995 ;
`270: 815-22.
`14. Beretta L, Grolleau A. La rapamycine : identification d 'une nouvelle
`voie de signalisation des facteurs de croissance, reglant le debut de Ia tra(cid:173)
`duction. Medecinelsciences 1998 ; 14 : 600-2.
`15. Conus NM, Hemmings BA, Pearson RB . Differential regulation by
`calcium reveals distinct signaling requirements for the activation of Akt
`K. J Bioi Chern 1998 ; 273 : 4776-82.
`and p7056
`16. Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivieres S,
`Mercep L, Ferrari S. Rapamycin inhibition of the G 1 to S transition is
`mediated by effects on cyclin 01 mRNA and protein stability. J Bioi
`Chern 1998; 273: 14424-9.
`
`____ 810
`
`Bull Cancer 7 999; 86 (7 0): 808-1 7
`
`NOVARTIS EXHIBIT 2043
`Breckenridge v. Novartis, IPR 2017-01592
`Page 8 of 9
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`

`La rapamycine et le CCI-779
`
`17. Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, eta!.
`Interleukin-2-mediated elimination of the p27kipJ cyclin-dependent
`kinase inhibitor prevented by rapamycin. Nature 1994; 372: 570-3 .
`18. Veverka KA, Germain GS, Dilling MB, Houghton PJ. Overexpres(cid:173)
`sion of bcl2 fails to protect rhabdomyosarcoma cells from rapamycin(cid:173)
`induced apoptosis. Proc Am Ass Cancer Res 1998; 39: 571 (abstr. 3880).
`19. Dilling MB, Hosoi H, Liu LN, Germain GS, Houghton PJ. Intrinsic
`resistance to rapamycin in human tumor cells may correlate with c-myc
`protein levels. Proc Am Ass Cancer Res 1999; 40: 4 28 (abstr. 2827).
`20. Beamish H , Williams R, Chen P, Khanna KK, Hobson K, Watters D .
`Rapamycin resistance in ataxia-telangiectasia. Oncogene 1996; 13: 963-70.
`21. Trepanier OJ, Gallant H, Legatt OF, Yatscoff RW. Rapamycin: dis-
`
`rribution, pharmacokinetics and therapeutic range investigations: an
`update. C!in Biochem 1998 ; 31: 345-51.
`22. Beretta L, Svitkin YV, Sonenberg N. Rapamycin stimulates viral pro(cid:173)
`tein synthesis and augments the shutoff of host protein synthesis upon
`picornavirus infection. j Virof 1996 ; 70: 8993-6.
`23. Gibbons JJ, Discafani C, Peterson R, Hernandez R, Skotnicki J,
`Frost P. The effect of CCI-779, a novel macrolide anti-tumor agent, on
`the growth of human tumor cells in vitro and in nude mouse xenografts
`in vivo. Proc Am Ass Cancer Res 1999; 40 : 301 (abstr. 2000).
`24. Geoerger B, Kerr K, Janss AJ, Sutton LN, Phillips PC. Rapamycin
`analog CCI-779 inhibits growth of human medulloblastoma xenografts.
`Proc Am Ass Cancer Res 1999; 40: 603 (absrr. 3978) .
`
`Bull Cancer 1999; 86 (7 0): 808-17
`
`811
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