Cobalamin
`
`Survival Tumor-Bearing Mice
`
`Influence of Cobalamin
`on the Survival of Mice
`Bearing Ascites Tumor
`
`NEPTUNE GENERICS 1007- 00001
`APOTEX 1007-0001
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`tumors.
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`Methods
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`Materials
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`NEPTUNE GENERICS 1007-00002
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`Table 1. Ellbci ofistvbalailiin ilcrivallwtzs
`Cm mg xurviya‘ if “ma bearing awim
`tumcrr
`
`Tm agent
`
`Dvzzsage. mgjlag bmly weightfday
`0
`25
`50
`
`(,"yar::>»:r:»b::i:zrnin
`
`1.8 2 3.9
`
`f),6:+;3.:%
`
`3.13313
`
`l‘«~'IEU’1:s=‘k‘{?ab‘.-l]i5lIT‘li[1
`
`8.0: 5.0
`
`13.6 :3; "Li
`10.97)
`
`Ill
`(£1.94)
`
`1?.‘-};r:;3.rl
`(€3.97)
`
`3 1:3 $2.8
`(1.00)
`
`11'): 3.2
`
`—
`
`f>.?:().9
`
`—
`
`19.3 .~.2:4.3.
`;' I133}
`
`2i).5:::3.7
`(H?)
`
`l§i.3x4.5
`{L00}
`
`£13 :*:0.5
`{l.0{}}
`
`lS.9:*:U.3
`H.063
`
`l?.3ifi.E
`(0.9%)
`
`‘lfherapvauzic
`“"""“‘
`
`-
`
`100
`
`13.? LS
`(1.06)
`
`20.5:1.=3
`(H?)
`
`lR.5:+'-l.3
`(1.03)
`
`3S.0:*: l l
`£33.} 3}
`
`:3
`
`33.3’: 9.?
`13.61}
`
`32.?:: lLl.(>‘-‘
`(3.18)
`
`mlcnosylcnbalamirz
`
`9,4: 2.4
`
`9.1 x Lri
`{LIE}
`
`8.9-: 3.3
`(MS)
`
`29.1 2 133*
`(3.53)
`
`20
`
`15.5:%:{}.‘~)
`
`16.7:%:4.:”a
`(1.1 I)
`
`2l.2:*:6.2?’
`(1.43)
`
`3&3: 10.3“
`(2.86)
`
`15.0: 2.3
`
`——~
`
`28.4: 13.7“
`(1.33)
`
`4El.’?:+:25.2l‘
`(3.83)
`
`SIT) sf samsival ti mes {days} fer re —~— ll). Significance of the ciiffarencre
`Hfaluvzs. an: means
`btztwxzen mntrol and axperimcntal values: “p «~:: 0,05; ‘*5: c: 0.01: Up a::; MIDI. Values in
`parentlwsss are ratias of mcfilan survival ‘time 91" test group to metdian survival time c>fwn~
`{ml gmup. A value ml‘ l.'?:3 or gr:-azser for a mat agrmt was mnsidcmd to demauslrate signifi-
`cant :i*S'li\*i'ij»’.
`’"l'herapeutic index is expressed as the mile LD5g;fED5m. where LD5{§ is the dust: lethal to
`30% OH pm.1ulaIi:}n and E1391; is ma: fiiftst’: then gives 23 ¥?ll‘%'l.» cell kill.
`
`remarkably nanmxic when adrztlinisterrzd lI11I'E1pEl’i1UI1C—
`ally. Thur: LDg,.;, for mclhylcobalamin was 3,800 mgjkg,
`boil},-* weziglu. which was 15 times the effecslive (1038. The
`LDsr.~ Fur S’~d::c:xyadcnos}-*lc<:>balamin was higher than
`that For methylcobalzmin. Ilowevcr. when a dose of 2,000
`mgfkg body weight was injecttzd inlcs tlaese mice. Ilkty
`startecl m 103$ waigllt. Thus, the value: cvl‘ 2.000 mgllcg
`body weight was used anti the therapeutic index Far 5'»
`s:ico:»:yadenosyl<:ubalamin was ‘.130. Altkmug.£1 very large
`clizvses 23$" cxabalamins injected inirapwitotieallga were non»
`tvxic.
`il
`laecamcs lxsthal when a maul": sm:.:lI~:?r (1056: was
`
`injecmd intravenausly into thus mouse tail vein. This; may
`be thr: effkict ml‘ the large mlumr: of Fluid cntfiring {he
`mouse blcsodgtream during 21 rralaiively shun perincl of
`izwjccticzn time.
`
`Vitamin 13;; and folate are involvxtd in the 1)l'DCs3SS of
`mac-carbomunit metabulism and methylcobalamin is a
`sourca 0l‘x)ne—c:arbon functional groups [.26. 37]. Althuugh
`the mechanism cal‘ the antitumor activity is not lcnown, it
`is quite evident that the rolefi of vitamin 3.; in carcino-«
`genefiis may be associated with its functions in normal
`nwetalmlistxi, paxfiiczzlazhs in tlwe:-: 0nc:»carb:3:1~11niI metabo-
`lism and in the positive and zzegatiwa mntrel of DNA syn-
`thesis by mtmnal and maligxxam Cells. [,?.(3. 2?}. Vitamin B33
`is expectad :0 current i.‘l€‘§:C1i¥‘€
`IZ>NA»th3gmim2 §?§a‘t}1l’ll:‘SlS
`in vitamin Bgg-defective nmrrow I28]. herzaxuse thymidy»
`late synthasfi rrzquircs NKN‘ll-math}?lenetetrahjwdrcefolata
`as mesthyl dtimilf. Fm the same reasen. in patients with
`folate and vitamin B;;_ cleficienty. thrz acisfiition of these
`vitamins 10 ['E1£i2'I'UW and ly:11pl1::myte culturss enhanced
`the incorpuralisn 0l'~*H~cle0x3=uridine Emu DNA I30}.
`
`l 06
`
`Tsaoflvf yashita
`
`C‘ol>alamin and Ascites Tamar
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`Downloadedby:R.Rachd-325?'18
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`NEPTUNE GENERICS 1007-00003
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`198,143,531«10516520156:28:42PM
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`

`
`References
`
`NEPTUNE GENERICS 1007-00004
`APOTEX 1 007 - 0004
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`-.2:
`
`Shimiarru N. Hamaztw R. Kanayama H1 Mafia
`M. Ragga S: Experimenial siudy uf antimnwr
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`Relay E): Eviizcégenic inhibézintzn and xfitTi3vt:7c urn
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`i‘¥8§;S:2t3Ei—2f_Vi3?.
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`<1? megadme \-'i13rm'n Ihtzrapy in an experimen-
`1:13 Tzrairi
`tam"-wr. Surg Neural
`l£«3$1:lf;:1€w1 ~
`2234,
`
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`acid and vitamin 3;; an gmwth <3? Rous lumnr
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`22?:
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`mic: effecz <5? vitamin B33 mu gwdimethylamiw
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`£‘35E1:74:3§4—855.
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`in hamstera. Vspr {Duke} E 960:6: I (3. 34-38.
`Yamanzoto RS: Effect m‘ vitaxnin 3;;-defi-
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`‘E’r-1:»: Sn»: Exp
`{SE93 Mud t980:1é3:35{?-353.
`MiIk:rf.Z(7. Ples::iaAM.Mi1I:-r IA, Hzaiclcibcrgcr
`C: The metabctolism ca? mcthytaied anzinnzao
`dyes.
`I. The d::m°r.rihyl:aiic>n cal‘ 3*-ms:1h3:i—z3-
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`(Them 19S3;I ¥?(>:8€n3—3?=$.
`'1'5ac:3 CS, Miyashiza K. Young M: Cylmoxic
`£1-Clitviijo‘
`(Bf mbalamin in cuttured malignant
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`58:293-396.
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`
`2*)
`
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`hlmtic him: marrnw: Eificxs nfhydrnxyfiag 5‘-
`&l€‘1‘):«;;mdexI‘C:s;~'H?>g3
`and mettvfl-Egg. mood
`l‘§?3;%1l:2E?‘3~3!)$.
`Das KC‘. Meznusssstis C. Herbert ‘v’: In mm
`QNA synthesis by bum: marmw Cclis and
`P}-IA—stimu!a1ed l1.’YnphC>C}a"E€3S. Fiupprnessisan by
`n-zmrzxxfiicaaxriivc titymifiimz -ufthe inirmrp-:3-mzicm
`-of ‘fiaxclrreawuridine into DNA; Enhanccnmeut
`nf inccrpewratirsn wtwta inauzirzquala vitamin B5;
`111? fcffalxr is wrrecmct. Br 3 Haemami 198i1:4:::
`51433.
`Buck L: Passi-
`Tisnmrt (30 Fiener \*‘. Ecanes
`bke potcntiation of flu-Bmpyrimimiins antiwtw
`mar Elcfik-'52‘)-‘ by p:::r<>:.~'!gluf:amiL* acid fftfflixi
`acid} and cyanombaiamin {B§l;L Clin Res
`IS33§:33:$S*3£x.
`
`I (38
`
`Tsacn’Myashi1a
`
`C‘¢3b;fi::min and Asciies Turmfzr
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`Downloadedby:R.Rachd-325?'18
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`NEPTUNE GENERICS 1007-00005
`NEPTUNE GENERICS 1007 - 00005
`APOTEX 1 007 - 0005
`APOTEX 1007 - 0005
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`198,143,531«10516520156:28:42PM