Note: Descriptions are shown in the official language in which they were submitted.
23 ~EEI '94 14:~2 P.6
3 7 '~
,... . .
A PII~RMACEUl'IC~ EXERq'ING A~!~q~U~ OR AC~IVITY
r'he imrentien portain to medicine, ln particular~
to ~;perirnental end olinical oncology and may be u~ad Inor
treat~ent o~ the hormone-~en~iti~e malisnant tumor~ in
5 women as ~Yell as in ca~es o~ the neclected oncolo~ical
I~ro~e.~.q t~rh~n the~e tllmor~ :lo~ their sQn.~iti~rit~ to hor_
mo~es .
Pharmaceutical~ are l~no~ Yhich in experimsnt~ in
~rit~o e:~ert cytotoxic e~îect~ on e.nim~l and human mali~-
10 r.ant cells pre~ent Q~3 ~usp.en~ion~ o~ indi~idllal cell~ inthe culture mediun~ or ~ a c~ll monolayer to ti~us cul-
~_ ture (see ~nventor'~ cexti~icate *or in~rention ~o. 7507~37
of 28.03.19~30 A 61 K 31/195 "A pharmaceutical e~ertir
antitumor acti~rity in vitro" by ~J.D~ Kislyako~ and
5 co-author9 ).
~ rhe~e are chemical sub~t~lce~ o~ simple composition
~Lnd Enothod~ o~ prep~ration, synthetic D~-~mizlo acid3
po3sessin~ a broad spectruT:I o~ cytotoxic e~ect~ Qn cer-
tain hurnan and an~ :nal mal~nant cell~ ~ D~-alanine, DI.-leu-
20 c~ne, ~-phenylalanine, DL-~lycine, D~-methionin~, D~-vry-
ptophan, and D~-Yaline.
In contrast to others, the ~yntheti¢ arnixlo aoid ...
~-valine in ..he experiment3 in Yltro exerts tlle ~tron~e~t
cytotoV~ic ~î~eot on mammalian cancer cells l,~Jithout an~
~~ 25 d~ age o~ non-rlaligIl~nt cells.
ho~rever, the GL~in a~d Yery ~igni~ica:nt shorlcor~inG o~
the above-~lent~ oned drug~, among them DL-vQline ~ con~ist~
i2~ th-3ir capacity to dama~e only indiYidual rns,li~nant cell~
~nd to e::ert no such e~ect in e~?erl~ents in vi~o when
30 thesQ cell~ for:n dense cancer ~iu~ors in ma~rLrnal~. ~hese
drug~ are not a~si.:lilated b~J t~:~or ¢~113 a3 readily a~ b~
Iree ~loatin~ cell~ the cullure ~diu~ oontainin~ ther~
There~ore the abo~resaid d~U~ require ccrtain conduotors
~Jhich could a~is l; cancer cell~ o~ den3e tu!TIors in ms~r.rr.~}s
: 35 to e.ssi~.ilate thet ~.
Pharmaceutioals are also Irno~m Yrhich we have selec1;ed
-- a~ the prototgpe and which exert ~Ln ~tiblastic e~ect on
~ " ~ ~ g ~
23 FEEI ' 94 14: 34 p, 7
2 ~ ~ ~ J ~ '1
. ~ .
the hormon~-~en~itlve ~Qli~n~nt tumor~ i~ women~ mammary
gland cancer a~d o~ry cancer tSee I;~.as~oV~ky, ~;D. in
"Ph~rrnaceuticsl~ JîedlZinQt' Publishar~, t"~,, 1985, part
I, p~ 5'~-603 and part II, p~ 470-471~. ~h~ are ~yiit~-
tically obtain~d 3teroid hormone~, deri~ative~ oi a ~trong
androgen, te~to~terone, th~ male ~ex hormone~ ~non~ these
pharmaceutical3, the followin~ have ~ound th~ wide~ cli-
nical applioation ~or trcatment o~ hormone-~u~coptible
mammary ~land c~ncer Qnd o~ary c~ncer ~n wo~en: testo-
~terone propionQte, medrote~trone propionate (or 2cC-~e-
thyldihydrote~to~terone), prolote~tone ~a ln~tU~e of'
204-~ethyldihydrotesto3teron~ ether3~. Oil ~olu~ion~ o~
the~e dru~s ~re inoculated intrar.~u~culax~ly~ In ~0l1~-te~n
treatrnent, ~ometlme~ another derivative to ta3to~ terone,
tnethyltesto~teron~, ~s given becau~e it- hQ~ a ~eQker ant~-
blastic eD~ect but i~ Qd~antQgeous becau~e o~ it~ oral
~sublin~ual) adt~lni3tration. All the3e hormones~Qre u3ual-
ly ~dm~n~tered in ~ery lar~e dc~s ~rom 50 to~:100 m~
daily, and are u~ed mainly in highly advanced ~tages ~ th
20 met~t~se~ of mammary gl~nd ~nd o~ary canc~rn~ ll th~
~bove-~e~tioned d~u~3, bein~ te~to3terone d~rlvati~e~,
e~.srt a ~ore or les~ mark~d andro~enlc ef~ec~ on ~he ~e-
m~le or~s~, r~ul'cin~, a~ter a long-ter~ tre~t~nent
with large dose~, in sever~.~ide-e~ct~, the de~elopr~ent
~' Z5 oi.general to:~lcity le~dln~ to th~ ~ollo~.vin~ côm~licat-
ion~s di~turbance.o~ wator-electrolyt~ met~olI~ xo
di~orde~ in the ~unotion~ o~ th~ er, ~idna~., he~rt,
hypercalc~rqi~ ~ndrome, a3 ~.7C~ noth~r ~Qt'O~ CmP~
lication ~or wornen~ na OL ~irillsm ~oci~ed with Q
h~h libido.
~or tho ~ fication o~ the ~ntitu~or e~fec~ the~
pharm~ceutical~ were or~inally t~ted e~p~ir.lental rat3
with D~.~A-induced ~nary ~l~nd cancer by 3uboutQneou~ or
I intramu~cular in~ec~ion~ oi oil ~olution~ o~ the dru~ in
¦ 35 a doae o~ 2-3 mg daily per ~ rat wei~hins 150-200 ~, that
bout 15 In~ bod~ woi~ht t~e Be~kro~nt, A.~ 'Anti-
tumor e~icao~ o~ hor~one~ in mammar~ gland cencer i9
rat3", Vopro~ oncologii, 1971, ~. XVII, ~o. 9, p~ 95 98).
1. .
.
.. . . . . . . .................. . .. .. . . . . . .
. . . : : ., . ,~- .. . .. ~ .,-, -
23 FE~3 ' 94 14: 35 P . E3
2 ~ 7 ~
~o the same group o~ antitumor drugs belollg~ methylte~to_
sterone adminlstered or~lly tho ant~blasti¢ eY~ect o~
YJh~ch i~ 2-3 time~ we~ r than that o~ oil-~oluble t~sto-
sterone deri~ati~es; there~ore it~ experimcnt~l the~pou-
ti¢ dose i~ about 25-~0 m~/lcg per day.
De~pite their antltumor e~fect on the ho~nono~~u3-
ceptible induced ma~n~ry ~lQnd c~noer in rat , all the3e
~ynthetic deriYQtives o~ testo~terone revo~lod in th~
experiTnents a num~er o~ signi~ic~nt shortcomin~J
1~ 1. In the pre~ence o~ sQveral cQncer ~no~ o~ ~he
Taa~n~r~ ~land in ono animal, mainly 3mall "arldition~
._ ¢~cer tumorq undentent resolu~ion ~Jhcre~ the '~nuin~
tumor~ which had achie~d Q controllebl3 ~i~e o~ ~bout
~.0 cm3 vlere con3ido~bly more re~ist~nt to the ~r~at-
ment~ .
2. Re~1~e~sio~ o:~ tile tu~nor~ in many ca9~ did ~iot
procecd to ~h~ erd, and ~nocul~t~on o~ the dl~,3 sa~ulted
only ~n th~ i~hibition o~ thc ~rowth, ~ ret;li3~0~, ~ol-
lowe~ by new irre~er~ible ~ro~vth o~ the ~ame tumor~.
3. I~ a ~ynthetic andro~en produced coT~plste re~-
re~.on of the t~tlor~ re~p~ o~ th~ tumor ~rowth were
lator observ~d on th~ sams site.
4, Rep~ated u~o of th~ ~ynth~tic Qndro~e~ ~vhich had
ori~al~y ¢aused regre~-lon for ;tre~tr.lent o~ ~e~rly fro~?r-
~næ tumor~ ter r~mi~ion.ox ~31QP~Ln~ tUmO1~ producad
no ~nti.t~o~ e~fcct, that i3, su3coptibillt~l to t1l~s dru~
was lo~t aorapletely.
5. ~Yl~h three oll-~olu~le te~o~terone deri~a'i~
te~to~teronc propionate, 2 ~-~e~h~ld-lh~droto~to~terone
propionate, and 2d~ -msthyldihydrote~to3~erone, mor~ acti~
~e than me~hylte3~0sterone, the par c~nt o~ ~en2ral reg-
~e~sion o~ all tumor~ wa~ ~0%, 70% and ~0~0, re~pectiYel~,
per ccnt of comp~et~ regres~ion (disQppear~nce o~ tumor)
10%, 50~0 end~20%1 re~p~c~ivelg, and per c~nt o~ partial
~5 decre~e of tumors 30~ 20~o Qnd 60pg r~spooti~ely,~ for each `~
;~ d~u~ a~ter 30 d~J~ o~ &dr.~ini~tration~ ~or ~n e~ec~i~e~sn- :
tltumor ao~ion the~e ~alue~ ~re low~ tllero w~r~ 60^~, 30~o
. ,.
...... _
Z3 FEB ' 94 14: 37 P . 9
2 ~
..... _
~ ~ .
and 20~' o~ tumora which did not re&r~s ~t ~ 'or ~a¢h
prapa~ation, r~specti~ely.
rl~ ~n~ into account all the abo~e-mention~ ortcom-
~ 9 0~ th~ pro~ot~pc~ we propo~e a now pharmaceutioal
producin~ ~ hi~h cl~nlca~ e~ct.
~ le p~armac~uticQl exhibiting the Qnt~tumor acti~ity
consi~ts o~ a mech~nical mixturs o~ 2-4 g o~ D~-valin~ an~
low nonth~r~ uti~ do~a ~0.020_0. 025 ~3) methyta~to~t~t~o~
~or u30 in ca~3c~ o~ horrlon~-~u3c~3ptiblo cancer tumor~ ln
lo ~tomsn ~nd o~ a mech~nical m~xture o~ o~ DL-~Qllna,
0,005~0~010, of' m~thandro~tenolo~e, and 0,3-0.5 ~ o~
p~thi~a~id ~or u~e.ln oa~o~ G~ c~ncer tumo~ not ~u~a~p~
tible to horrnone~
Thu~, the in~en~ion i~ ncw bccausc it i~ unlmoY~ ~t
~5 the current level o~ med~cine deYelopmont. i~h~ in~nt~a
level o~ the propo~ed ph~rmaceut~cal po~e~ing ntitumor
~cti~it~ doe~ not clearly ~ollo~r ~ror~ the lsvel o~ de~e-
lopment o~ current chemot~erapy o~ the hor~on~-~u~ceptibLe
malignant ~umors in worlen tt~e prototypo).'~.$he i~ention
ma~ p~acticall~ be u~ed on a largs rc~le ~or.succe~ul
therap~l in outpatient ~Jarcl~ o~ hormone-su~ceptible malig-
nanttumor~ in women, ~ve~ ar adYanced csa~e~, when thi3
ho~one-~u~ceptibillty rnay b~ coTnpl2tely lost ~nd all ~h~
con~entional m~thod~ o~ chemo-hormone-the~apy becol~e ir.
~_ 25 ~L~ecti~o.
~ he ~ucces~ul application o~ ths n ~ harmacautical
may be due ~o it~ ~tron,~ anti~la~tlc prop~r-t~es, it~ effec-
tive action b~in~ completely ha~nl~, a~ its pro-
p~rty to enh~nce the p~tient 13 de~ence forc~ ~nd ~o ~er~
a ~trong anal~etic e~ect.
~ he es3ence o~ the in~ention i3 pro~nted by the en-
t~rety o~ the e~entlal ~eatur~ su~icient ~or th~ achie~
~ement o~ thc nece~&ry result.
~ or theoretical sub3tant~at~0n o~ the proport~a~ of
tha ~lle~ed pharmaceut~cal and con~l~mQtion o~ the no~elt~
~nd th~ inven~e lev~l o~ the propo3ed invention, th~ new
antitu~or dru~ W~3 tcsted experimentall~.
`""' '' ' ;'~ '
, , . , .: . , . , i , . ~
Z3 FEB '94 14:3~ P.10
-- 5 --
~Yhon u~od Yor ~ro~,tlr.~nt a:e hormon~ u~ilcePt1~
induced m~mn~r~ ~lan~ cancer tumor~ in ~om3le rats, the
proposod pharmaceut~c~l consists o~ ~ msohanical ~i~.ture
o~ 500-550 mg of synthetic ~m~no acld D~-~aline ~ld a low
non-ther~poutic do~e of 5-20 m~ methylte~tostero~e Per
kilo body wei~;ht of tho aniT~al administered daily by the
oral route; in oa~es o~ lon~ ~rowin~ m~mary gland cun-
cer tumor~ in rat~ Y~th lo~t hormone-~u~ceptibillty tho
new antitu~or drug con~l~t~ o~ ~ mecha~ical mi~ture o~
500-550 ~ DL-valina , 20-25 mg o~ ~abolic hormone
Meth~ndrostenolone, and 40-50 m~ phthiv~id per 1 k~ ~o-
dy weight per` day.
In all ~er~io~3 of the ~ev~ antitumor dru~ ~pplic~t-
ion it i~ ~ecessary to keep a prote~n-rich and ~t-poo~
diet.
~ he e~perim~ntal data obt~ined in the ~tudie~ of
the inmo~t meohanisms o~ th~ ~ntibla3tic e~ect on canc~r
t~mor~ o~ ~he.ne~ anti~umor dru~ i~ the form o~ mechan~o
; mi~tUrB3 0~ aminO a~id ~L-V~ e ~nd 10YJ no~-therap~uti~
2~ do~e~ of andro~cn~ - m~th~lte~to3tero~a or met~l2ndxo~tsno- ' -
lone (an an~boli¢ with very waak ~n.dro~enio propertie~)
I ~howed tha medi~tory role of the3e hor~ones ~or D~-valine
! required fox t~e a~imilation thereo~ by c~ncer c~ or-
¦ min~ don~e tu~or~ ~n ma~nal~.
~he li~it quanti~ati~e ~alue~ o~ the ~nlxuure co~po~
nonts depe~d on the degree o~ act$vity o~ ~he en~ire ~n~
tumor prepar~t~on. A~ ~hoYm by the expe~ ental ~tudie.s,
the optimal do~c of D~-vnline is 550 m~Jk~ 3 decre~e
. to 500 m~/k~ has no snEluenc~ on ~t~ e~ect, nc~Sther doa~
Fs ~urther incre~e o~' the do~e, ~or in3tance b~ 2--old,
A decreas~ o~ D~-vallna do3e belo~ 500 ~g~kg wors~n~ the
~ntibl~stic ef~eot o~ the mi~ure and with Q.do~ 2-lolA
lower than the optim~l ~275 m~fkg) thS3 regres~ion e~eet
dicappear~ ¢ompletely~ ~he non-therapeuti3 do~e o~ ;nath~rl-
testo~terone o~ 5 m,~ per kilo body ur~ight i~. combin~tlon
i with ~L-valin~ giY3~ the optimal antibl~s~ic e~ct on
. ir~uced c~ncer tumor~ of the ~lz~ of 4.0 cm3 to 6.0 _~3
ulhich stlll have Yery h~gh ho~mone-ssu~GeptibSlit~ l','ith
:
.`
~` ~ A~ r
23 FE13 '9'1 14:40 P.ll
~ ~ C ~ ~ 7 ~
..... _~
- 6 -
~urther growth o~ the tumors the horl~one-~u~ceptibilit~
docllnes, ~nd ~or tumor ~i~9~ over 6.o cm3 up;~o B~10 cm3
it w~a~ ~ound better to u3e D~-valine in col~blnatio~ Wit}l
methylte~to~terone, 10 m~/kilo bod~ r~ei~ht.
~he~e optimal do~e~ o~ meth~lt~tosterone are con-
~ider~d to be nontherapeutic becau~e they aloncl without
DI-valine, cau~e no re~res~ion or aven lnhibition o~ the
gxo~th o~ the hormo~-euscept~,ble mar.lm~r~ nd cuncer
tumor~ in ra~ ethylte~to~terone alone cause re~r~-
~ion o~ ~ch ~xperiment2l tumor3 only be~inn~n.~; ~ith a
dose o~ 25 m~lc~ body wei~ht, and re~re~on ~3 thi~ ca~e
~ho~3 ~11 the abo~e-mentloned ~hortcomlng~ o ~t~ anti-
blastic e~ec~ o~ oil-solublo testo~t~rone ~ do~ri~rs,ti~re~ ~
tth~ prototype), Accordins to our data, tho m~chanica
15 mixture o~ ~-Yaline ~th 25 m~fl:~ methyltesto~t~rone has
l;h~ ne sho~tcomi.n~ o~:' tih~ ~ntlbla~ l;ic e~ ec~ but le~s
marl~ed th~ in the proto1i~yp~. ~ do~e o~ methglte~tostaro-
no belo~r 5 ~k~ ¢ombinatlon ~rith D~ rQ1i~e produce3
a 3~ icantlS~ 1O~;Jer ro~re3~ion o~ tlle hormolie~u3cep-
20 tible cancer twnors in rat3.
In exper~ment~ uritll sim~lar lon~-tar~ gro~nz tu~or3
1~ or~3 or l~r~er in ~i~e whioh have parti~llg or comple~e-
l~r lo~t their andro~an ~u~oeptibll~tiy a ~och~nio~l mixtu-
re of DI-v~lina ~Jith ar.other ~ery weak ~ndroon, ~oth~-
Z5 drostenolone, in a do~e o~ 20-~ m~ body ~l~ht wa~
~ound to b~ optimal. A 2-fold cl~cre~e o~ tha~do~e tl2~5
mg~kg) in mi~ture ~th D~-val~no lnst~ad o~ ~ære~3ion
o~u~ed ln~igni~iaant i~l~b~.tion o~ $row~h of ~h~a c.~ncer
twmor~ Qnd an incroa~ ~ad no e~Lect on tho X~.sulta.
Ho~e~er, re~e~ion o~ e;c~erimont~l c~ncer tumor3
in r~t~`tr~at~d ~r th ~ mi:~ture o~ D~-v~line ~rith tne-th~-
drostenolone ~lone wa~ e~l;rer.l~ly ~low, ~o t~at in 30 da~J~
o~ the experiment ~11 the t~nor~ re~re~ed only by 30~_
71~ o~ its original ~ze~ ~nd on the aver~se by only 52C~o
(~ble 1),
PhthiYa~d, ~ kno.~ dru~ for tub~rculo~is r~ith a
~on~ m~ brano~ropic ef~ect, ~l~s ~oun~ to be capQbl~ to
incre~o con3iderabl~ th~ conductivi~y o~ DT~ llne by
.. . . ... ......
~3 FE13 '94 14:42 P.12
- 7 -
~etha~dro~tenolon~ ~nto th~ cells o~ lo~-term ~ro~ng
den~e tumor~ ol rat ma~nary ~lQnds. rl'he optim~l do~ o~
phtllivnæld ~a~ ~ound cmplrlcall~ to b~ 45-50 ~k~ bod~
wo~ht. A co~sidera~le ~ncrea~e or dccre~ o~ the do~e
eith~r does not af~eo~ th3 tumor growth or may even ~nhan-
c~ it.
~'able 1
A phr~aceutical e~ertin~ antotumor~l acti~lty
~ ite random-bred ra~ ~th induoed m~mnary glQnd
cancer.
~reatme~t: D~aline (550 m~tkg) ~nd methandro-
~~ ~tenolone ~25 m~ ) in com~ari~on with
untre~ted t~nor-bo&ri~ ~nim~13 (condi-
tional tumor size~ in cm3)
15 ~,~ Initial I n t e r v a 1 9
I~o. dat~ Je~lc 2 ~leek~. 3 weelss 4 ~q~
CON~RO~ GROUP ~untrea~d)
1 4 7,~ 20.2 37.3 died
2 ~9 5.7 7.0 .13.3 20~
20 3 a~ 6,o10,2 16.0 25~1 d~ed
b) 5,05vO 5.3 B.2
4 5.16.6 7.l 7.~ ~.0
; 5 7-312.5 19,0 30.2 42.0 ..
6 a.o9.6 20,0 ~6.0 di~d
25 7 ~,84,5 9.5 14.2 23.0
. 56 ~ 2 7 ~ 3 1 0. 3
t~h 5,.3~.7 11~6 ~n.2 20.7
~ean and
~ariat-
- io~ ran- .
30 ~ 3.~-~.0 4.5-1~.5 5.3-~0 7.~-37.3 a.O-42~0
P: compari~on <~0.05 <0.01 <0.01 <0.01
~th lniti~
,~
P R O G P. E S S I O IT
. ' ~::
. ~
23 FE~3 '94 14: 43 P. 13
~_ 2~3 ~3 ~1 ~
Tablc 1 ~cont~nued) : :~
R~t~. Initi~l I n t e r ~ a 1 s .~,,
No, tlata 1 r~ek 2 weëk~ 3 weelc~ 4 ll;e~Ls ~ re~
re~-
~o~
EXP~I?.~ r~ I, GROUP (DIJ~ ne L~nd metllandro~
~tenolon~ )
4D6 ~4 3.4 2"1 2~0 56
210.5 11.2 6,9(nec- 6.1 5~ 52
ro-
35.5 5.7 ~7 2.8 . ~ 2~3 ~o
4 7,2 3.4 ~.6 2.7 ~ 2,1 71
55.2 ~.0 2.~ 2,5 ~ 2.~ 57
61.7 5.8 5.5 5.8 ~ 5.5 30
7G.6 6.3 5.6 ~.6 4,2 36
6.3 ~,0 .~0 4,3 , 3.3 50
1~ 9 4.5 3.7 3,6 2.8 ~i 2.0 53
mo 1;~ o 6. 5 5. 3 ~ ~ 3- 7 ~ ?,. ~ 52
moan . . . . ~.
ana VQ~
ria~ion 4 ~j 3~0 11,2 2~-649 2.~-6.1, 30-71
P - ~>o,05 <0,05. <0,01 -. ~0.
. 2 0 . PL E ~ P~ E S S I 0
P - corapar~on o~ eaeh ~r~e~: witll th~`~it~l da~a.
oompars.t~e analg~ w~th th~ pr7~otyp~ - oil-~olub-
1~ synthe~lc te~-.,ost~rons dcriYati~s~ ~lnisterad ~ n-
t0r~ donc on the baæi3 o:f th~ Rxpo~m~ntal d~ta sho-
25 ~Jed the ne~r s,ll.e~,Gd ant~tur.~or dru,s,r to b~ Ri~;nilicantl~r
erent Irom t}la kno~vn on~
1~ ~rl~ alle~ea antitumor dru~; e~rl~ the anti~la~ tic
e~Ieot b~ t}lo close interaction of 2 componenl;~ OI a rnech~-
nical ~tu~c: DL-valine arnixlo acid capable o~ roduci~
30 Qn idependellt cytolysi~ e~ect onl~r ~xl indl~r~du~l mar,lma-
$aTn c~ cer c~ in Yitro and a~ ~ndro~.3en o~pi3ble o~ per-
~orm~n~ in ~ ~T~ nollthor9,peutlc do3e J~113 role o~` t,h~ con-
.
~ , . .
~ " " ~
-
23 FEB ' 94 14: 44 P . 14
- ^` 21~.6a7 1
ductor o~ 3 ~no ~cid i~to .,h~ cell3 o~ ~ ~ol~d m~nuna-
lia~ tn~liænant t~nor.
2. ~he ~ e~ the m~chanic~l mix.turo ~Yith
D~-~aline aclino arCl~ contal~n, in co,npaxison wlth tho pro-
tot~,rpe ~25-~',0 m/l~), Q lottr (5-10 m~X~) ~o~ltl~er~peutic
do~e o~ a 1;e~to~JI,3ron~ deri~rati~e, methyltesto3teron~,
e~orting no ant~bla~tic e~fecl; ~Yithout Dl,-v&line,.
3, ~o n~YJ ~nl;itumor dru,~ d~ers oon~iderably ~OT:~
th~ p~otot~rp~ al30 by ~highly ~`ecti~,-e antibla~tic s,c~
10 l;ion:
a) in t:he pxo~ence o~ se~roxal tutnor.s in ~ anin~Ql,
tha '~m~in" tumor~ ~ioh ha~e ac}~oved ~ con~roll~ble ~e
~4~0 cm3) under~o resolut~on :~il"St 01' ~ m~Ulta~l~lOUi~ly ~Jil~.h
l'ædditional~1 onos;
b) ~o disconti~u~tion of re~re3~10n, or occux e~ce
oi' xel:~ia3ion ~ollowed b~ ir~ttexsible tumor ~J,ro~th i.~ o~-
8erved upon adminis~rD.tion o~ ~he ne~l prep~tion;
C) llo r~lap~es o~ turnor growth ~ ob~erved ~:~ter
oo~plete resolu~io~ ther~ol;
d~ in repe~ted u~o o~ the ne~J preparation, no l0313
o~ sen3it;i.vi.,3~ to ~ t i~ ob~erved;
a) daily ~dmi~istration îor 30 ~ay~ o~ "he propo~od
preparat~on producs~ the re~;~es~ion ef:E~ct r~lated ~Lth the
de~oe OI tumor hormone-~3u300ptibilit~J and meth~Jltestost~
25 rone dos~ Yith a do~e of 5 ~g/kg per cent o~ general Y~eg- :
~e~sion ~ 89% ~10%.o~ tu~or~ did not re~ol~e - 2 out o~ :
17); cot:lplot~ re~re~sion tdi~pp~aranc~ 0~ tunors) wa~ ob-
~arved lrri~ G55~ of tuDIo~ (11 out ~ l7? and p~rtial re~
ra~ioll (b~J 53%~85$ o~ the in~t~ e o~ the t;umoY~) :
30 ~rith 2~%, th~t ~ r tumor~ out o~ 17 tsee ~s.bl~ 2~; rrith
~o~e o* 10 mgJI;g ~oneral re$~e~sion rla3 ob~erved urith
100S~U of tl,;mor9~ thal; is, all the t~ or~ ~93ol~red on tlls
~ r~go by ~30~?7, oo.~r.plet:e r~:Tr~ssion with 20%, a~l in ~0%
o~ the tumor~ r~olution achie~Yed 61% to 955~ o~ tho i~$-
35 ti~l size o~ 1;he tumor wihin 30 day~ o~ tn~ e~p~rirnont
(~e ~,3~1~ 3). ::~
4. ~.h~ Qlle~3ed a~ltitUmor preparal;ion, in co~tr~3t l;o
23 FE~ ' 94 14: 46 P . 15
2 ~ ;3 7 ~
- 10 -
the prototype and other kno~m oyto3tatic~, alon~S~ld~ r,ri1;}
~he re~ol~in~ e~ect OIl ms.lign~ll; I;w~or i~ al~o capable
i;o enh~ce the de~e~ce ~orce3, ~,1. r~ tanca to ~lmor
o~ tlle tumor bee,rer, ~ indlcated by:
a) ~ ni~icant incr~a~e in the boày ~r~i~h~ OL tho
a~imal Rccompany~ng t~3 re~re~io~ t~ee ~able 4~;
b ~ ha~mopoieei~ ~timul~tion lea~l~g ~c. normali~at-
;io~ .ereof ln tlle courF~e o~ twno~ re~re~iorl tsee ~'able
5);
c ) a si~ni~iG~nt increa~e ~2-3-~old) OI t;h~ ~u~
~ral ti~le oi~ the arims,ls in ca~e~ e~ C~1t l~
tumor e~ect achiev~d in 30 d~y~ o~ tll~ e~perl~ent Q~
cor~pared with that oî cont~ol (un,,~e~l;ed) ~nl~ a~t;er
t~ ination o~ the e~p~ritnent.
. ~able 2
A phQrm~c~utical e~;ert;lnz antiLurl~.ora~ ac ~i~rity
Induced m~ ary ~ nd c~cer ~n r~ndom-b~d ~/hit~ ~erns,le
rat~. Cond~tio~l tu~lor ~i~ec3 ~in cm3) in ti3:~tms~t l,~it'n
5 m~sJ~;~; snethylteeto~terone ~r.d 5~
Re,t.I~litlal ~umor ~ze~ ~Liver ~n~,e~v~l.s o~.
~o. da~,a 1 week 2 w~ek,s 3 w~ek~ 4 wo-
elc~
CO~ROh GP~OIJP (u~.,rea'~s~)
~.D, .7,5 11.5 ,c ~ 21.,3
'2 4.6 6,~ 7.1.~ 7.1 7.3
3 7.2 ~ 8.4.1~ 14.~ 17.2
7.~2 12.0 1~.2~ 30.5 5~.~
~,1 9.3 22.1 ~ 3Z.4 di~d
G 3.9 ~,22 23.~ iecl
- 7 3.8 5~3 ~ 15.a 21
. 30 ~ 3 3.S 5,~ 5.9 6.7 9,6
: 0 1, ~ 2 .. 7 4 . 7 9 , 7
9 6 ." ~12, 5 13 . 3 1 S . 1 21
~'~3 G.3 2~5 35.5 ~led
. ~O.Oe' ~QtS~ 10
~5 I.lorS ~' __ ___
!~
23 FE2 '94 1~: 47 P 16
2 ~ 7 ~
....... ~ _
-- 1 1 ~
~abl~ 2 ~conl;inuod3
. _
Rat.Initial ~umor gi~se~ ter intervs,l~ o~
No. d~ta 1 week 2 wsek~ 3 week~ ~, w~ei~
Arithm~tic 5.2 7.5 12.7 13.7 ~0~8
mean and
~raria~ion ranses (3. 8-7 . 2 ) tl . 8-12~ 5 ) ~2 . 7-23- 4 ) (4 69-; t~ 3-
P in compari~on ~0.05 ~01r01 ~0.01 ~0.01
wlth initial
10 datc, (be 1rre~1~9
in ¢ontrol
eroup )
P in compariBon
15 o:~ control end
experlm~nt~l ~ 0,05 ~0.01 ~0.01 ~;0.01<0.
anlm~l~ (by
~teeks )
E~ JT~L GROUP (treated ~ith the p~apax- :
~tion)
R~t~Initi~l ~or ~3iZ9S a~tex intcr.tr~l~ o~ :
~JO. dF''I;Q 1 ~'IL'~3 2 l~r}~3 3 r,rl~ 4 ~Jk~ % re~-
~e3~3-
0~1
1 4~ 2~0 0,81 O 0 100
2 4~2 2~2 0~7 0-4 100
3 4~1r 1~0 0~0~1r 0 0 100
4 4~0 0~8 0,0~ 0 0 100
5 a) 5.6 ~.~ û o O 100
3~ b) 1.0 0.8 0 0 0 100
,6 ~,~9 ~,7 3~8 2v8 1.0 80
7 4.~ ~0.4 0.1 0; 0 100
:8 a) 6.4 5.3 ~.8 2.9 3.0 53
: : b) 0~2 0 0 0 0 100
9 : 4~7 3.5 1.1 0~1 o 100
~'
'
~ ~ .-: ", . . . , : ,- ,.
Z3 FE13 ' 94 14: 49 P . 17
- 12 -
~a~l~ 2 (oo~t~nuod )
R~. Ini~i~l D.r.o-~ ~Iz~ ~% r~
5, 7 3 . 2 2 ~ 2 1 . 0 0- 10~
11 7.6 G.5 3.9 3.5 2,074
. 5 1~ ~7 3,,2 2,3 1.2~ ~75d5
13 7,8 4.G 5~1 2,0 0 100
14 a) 6.2 7.3 7~5 ~.7 10.7
3 ~, 2, 5 3 5_ .
~o. O:e , .
_ rats~tu
mor~ 1
__,_ ,__ "_ ,_ , ,"_ _ __ _ , ... ,, _~, ._.. __ , .,.. _, ~.. , _
~ithmoti~c ll~7 3 2.1 1~5 : 1~2 82rj~
'Q,at~Ldn ~o~ 2-7 . 8 3 tO-7 . 3 ) tO-7 . ~ ) ~0-~. 7 ~ ~0-l o. 5 ) (o-1 oo )
rQnge~ j, . ... mor3
p in coT~pari~ , I;um.
son t~i"h in~- <0,01 <0.01 ~o.ol <~,01 ~>50S~
t~ al data 2 tum.
(by ~e~ks in . ~with-
20 ~:~?cr~r~ental .. out
. ~;roup) . ~ s~ sn~
b) se~rer~ ~ur.~or~ ~ n o~o ~nt:.
.:
. .
23 FE13 '94 14:50 P.lE
, 2.~ 3
.. - 13 -
T~ble 3
A pharm~ceutlc~l ex~rtin~ a~titumor~l acti~ity
Induced ~mm~ry ~lQnd a~ncer in random~bred white mic~
(conditional tumor ~iz~ in cm3) tx~nted Y~th 10 m~/1Cs
~ethylt~sto~t~rone and 550 mg~1cg ~-v~line _
5 R~t. Initial ~umor si~e~ a~ter intor~al~ o~ _
~Jo~ data 1 w~k 2 week~ . 3 we~ 4 woelc~
G~NTR0~ G~OUP. ~un~reatsd)
1 4 7.8 20.2 37.3 died
2 3,9 5~7 7.0 13.3 20,2
10 3 a) 6.0 10.2 16.0 25.1 di~d
~) 5-0 5-~ 5.3 ~-2 . :
5.1 6.6 7.1 7.8 8.1
7.3 1~5 19.0 30.2 42.0
6 8.0 9.6 2000 36.0 di~d
15 7 3.~ 4.5 9.5 1~2 23~0
a ~.5 6.2 7.1 8.3 10.3 ~ : .
Ax~thm.
meQ~ ~nd 5.3 8.7 11.6 20.~ 20.7
Yari~tion
20 r~n~e~ ~3.~-B.0)(4.5-12.5~ ~5-3-20? (7.8 37.3)(a.0-~200)
a~ com- ~ .05 <0,01 <0,01 c~0.01
pQred ~th
~nitial data
_ P ~ 0 ~ R E S S I 0 ~J _ _
~at. Initial Iu~or ~ize~ a~ter in~erv~l~ o~
~,o. ~a 1 ~Jee~ 2 ~reeks 3 we~k~ 4 ~eeks qO re~-
r~_
~ion
_ _ .___ _
~P~RIL~TTA~ GRoUP (D~-~alln~ ~n~ me'h~l-
te~o~tero~e)
30 1 6.8 3~20.7 0.8 O.B 88
2 ~.o 4.3~.0 3~ 6~
3 4,2 3.o2.3 o.~ 0 100
~ 7,o 8.66.9 3.9 2.0 71 :~
7.3 7.45.0 2,~ 2.5 66
Z~ FE~ 'g4 14: 52 P. 19
& ~i 7
- 14 -
~able ~ ~continued )
6 6.7 ~.1 2.4 0.9 o.6 ~5
'1 7~,1 5.0 2,2 1.0 0.9 a7
~.Z 6.~ 5,0 3.3 2.~ ~6
9 5,~ ~-o 2,3 1.6 0 100
7-5 7.8 5.G 4.1 2,9 61
., ,,, ~, ,.. .. .~.. .... ~ .
AritlLm. 6. 3 5~ 4 3~ 6 2 . 1 1~ ~ 80
m~n a~d
~rLo.~ion
10 r~ges ~4.2-8.2) (~.o-~.6) (o~7-6~9) - . tO-2.9)
(0~ ~-4.1 ) (61 -1 00)
P a~ com- .
pared ~th ?0.05 <0.01~<0.01 ~0.01 2 tu~n~, .
inLtial . ~: 1007
1~ d~ta . ~ll
" ' O i,~
.~ 50%
1~ ~ G R E ~ ~ I 0-~
5~bl~ ~
A p~l~rmaceutical e~rtin~ titumoral ~ctL~rity
Induced m~rn~ry 6land cancer in r~ndom-bred ic.l~2le
~, ~ rat~ . Uei~ht chan~e~ (in ~,) o~ e~p~r.l~1;al ra1;~ ~
~,r~ated ~,~th 5 mg ~eth~3.testosteron~ ~nà 550 m~
25D~-~alinc p~r k~ bo~y ~lei~ht and c~trol a~l~m~
(u~;ro~ted ) during on~ month -.~
~;ti'$R~J~ OUP (A~ imal~ th ~nor re:l,r2s~io~)
'.Y3~ we~
~lo~ Pl ~ wa~c 2 3 4 ~a
w~el;s ~ck~ w~3k~ 1 mon-
1 220 230 2~0 245 250 ~3
2 260 265 270 270 275 +15
3 24 0 225 260 260 265 ~25
4 200 210 215 220 220 ~20
35 5 200 210 220 235 2~0 ~40
. ..... ............. ~ '
F~
23 FE13 ' 94 14: 53 P . 20
71
- ~5 --
~s;bl~ 4 (continued) .
6 160 1~30 18; 190 195 ~15
7 200 210 215 220 230 ~30
~3 240 2~0 245 250 2G0 ~20
~ 220 220 230 235 2~0 ~20
2~0 255 260 260 255 ~15
1 1 170 1~0 190 190 200 ~30
Ari~hmet. 213 ~20 230 234 239 ~23
variation(160-260) ~1a~2~t5)5 27()9 (195-275)
P a~ r.OT;lpQ-~o,o5 ~,0.
red YJit~l
~ init;~al
tby w~eXs~
15CONI~R0~ GROUP (with pro~re~ion)
R~t.Ini- ln 1 in 2 in 3 ln 4 ~rteeka ~ i;t los~
~o, tial w~elc wee'.ca wl~ we$~ht~ o~ in 1 Tnonth
tD~ ani- with
~al mor mal mal tu-
wi~h- wlth- mor
out out
tumor tu-
~ ~ mor~ _ _
2go220 240 24 0 25020 Z30 -20 -0
2 250230 230 2~0 240 6 23~ -16 -10
3 220215 290 2~5 2002~ 1~0 -40 -20
4 240230 220 235 23050 1~0 -60 ~10
200.190 195 190 1~020 160 _~.o-20
6 2602~0 250 230 24020 220 _~o -20
Arit~;~. 23G22~ Z37 23~ 200 _36 -13
mea~ and
~rari~t-
3 ion ~200_~190~ .,5- (190- (160-234~ (0-20)
ran~ es ~60) 260) 2 9o) 285)
P as ~o~- ~0.05 ~0~05>0.05 <t)45
pared with
. init~ al tbY -
weck~ )
, _ . _. _.__,.. ... .............................. ~,
Z3 FE13 ' 9~ 14: 55 P . 21
2 ~ 7 i~
.. ..... _ ..
- 16
qlable 5
A pharmaceutical exertin~ itumoral ac~ivit~
Stimulation o~ he:mopoie~ ccompanying ~unor ~e~
sion in ~emale rat~ witll induc~d manunary gland cancer
tr~ted w~th DI-Yaline aIld msthylte~tosterone (~;ho
~on-parametrical method o~ ~atl tical tr~atme~t by
the "I" criterion of Wilcockson-;tla~n-Witney. ~he
me~n valu~ and vari~t~on r~n~ ar~ presented),
AniT~al Hemoglo- Erythrocyte,~ ~ucoc~e
10 ~roup3 bir by in 1 ~m3 in 1 mm
Sally~
~' - te~t
_ _ _ ... ...... . ...... .. .
--~ 2 3
I
-r~ormql ~7 4534000 5300
(10 anim~,l3)(84-90) ~402000û~4920000) t4000-6600)
II
Controls `76 4165000 ,'9650
w~lh tu~or~ ~4~-96) (3100000-4~00000) :(7~00~12000)
20 (untreat~d) .
P in compari~
son OI ,~rou~s ~ .0 ~ 05 > . O . o~ ~0 . 01
~ I snd II
III . ;~
~5 ~ .pQ~imental ~ 91428 . -.~057
~rith tur;lor~, (66-g4) (3820000-4710000) .:(6900-13500)
treQtod
P ir~ compari- ~ ,~ ~
~on o~ $roup~ ~0.05 >0.05 ~0.05
II end III
. _ ,_~_._ .__. ___._", .. _ .. ~_ .. _.__.. " .. ,, . ___.............. ~ .
P i~. compar~-
~on o~ ~oups ~o.05 >0~05 ~0.01
I a~d II-~
. . _ ,__ _ . ~,,__. ~
: ITotes ~ increas~, - Y decrease 9 r- - unchallged~
. ~:
23 FEE~ '94 14:56 P.22
~` 2 ~ 7 ~
.... .~ ._
~able 5 (continu~d)
Animal ~o~ino-Stab So~,m~n- l~lono- ~ympho
$roup~ phil~form~ te~i cyte~ cytes
1 5 6 _ 7 ~ _, 9 __ _
Normal 2,9 3. 4 38,7 5.6 5~.2
(10 a~imals) ~o-6~ t2-7~s) (19-56) (2-8) (36-6B?
II
~ontrol,q 2~6 7.2 62 1c7 27.~
l,~th tumo~ (o-5~ 0) (4-11 )(56 6B)(1-r~) ~22-35)
-- tUntreated ) ~ __," ,,_ " ,,,,,_,_
p in comp~ri- ~ + t
~on of group~>0,05 ~0,01 ~0.01~0.01 . ~o.ol
15 I and II ~_~ __.~....~ .... - -
III
~cp~r~ental 2. 0 3. 6 45 4.7 43
~Yit}l 'tllt;lOY'g ~ ~0, 5-4. o) (2, 0-5. 0) (31 61 ) t2-~) (31 59)
treated
20 P in comps,ri~
~on o~ ærouP~ > 0.05 <.Q.5 <0.05 <,0.05 <0.01
P in compari- ~ ,_ ~ .. ~ ~
son o~ ~roups ~ 0 . 05 ~ 0 . 05 ~ 0 . 05 ~ 0 . 05 > 0 . 05
25 I ~nd III
~ ,............................................ .
I~o~e~: ~ a lncreQi~e, ~ ~ d~or~a~e, ,-~ a unch~l3od,
`i.' ' ' ., ' ' ": .' , ,.:. ., . , . '' ~ ' . . ...
- - Z3 FE~ ' 94 14: 58 P . Z3
2~ ..37~
- 18 -
~able 6
A ph~rmacoutical e~csrt~n,~ ~ntitumo~l aoti~rity
~lle e~ect oi~ ~ mixture o~ D~-valin~ ~550 m~/k~),
methandro~tenoloIle (25 ~g~lcg) and phthivazid
t50 clg/l;~) on l~r3e .~ tumo:r~ (or on several tu~
mor~ ~n one animal) of induo~d ms3n.~ary gl~nd cancer
~n ra~dom-bred white rat~ . tConditional tumor ~ize~
in cm3)
. . , ~ . . . _ . ~
I. It~eated Qnim3l~ (e~,~porimenta,l)
R~t Mo . Ini - At- ~ n ~ :3rvg,l~ t;J~ ) c~ re~
~l 1 2 3 4~ 5 6 ~lo~
a~ 18~5 8~410.3 11.9 11.3 6.2 8.9 52
~) 1.6 3~3 2.1 5-5 4.~7 10.2 8~5
2 24.0 2g.6 23~.9 16.5 4.4 ~.9 6.~ 73
~c~o -
s~ ....
3 11.D, 10.. 9 11,4 1~.1 . 1~;J5 2207 ~1,7 -
~) 10,8 7.~ 4.3 both ~u- 2 togai 2 toge-2 to- 75
~ed ther ther ~e~
.'.; thsr
b) 3~Z 2.7 1.0 -3.4 -~.5 -3.0 -3.5 .:
~)1Z~5 6.2 4.3 1.9 i.2 o 0 100
b) . 0.~ 5.0 2.7 2.5 0 0 100 ~ .
6 12.0 12.2 4.~ 0.,8 0 ~: 0 0 100
necro- .. ;. .
7 a)16.5 7.3 4.3 3 tumor~ 3 to~- 3 ~0~2-
~u~ ~d ~hor ther
2 5 ~ n t o o ~
b) 3~7 2.9 1.6 -13.4 -20~0 -21~5 -
c~ 1.û 1.9 3.7 -19~2
~)10.1 8.9 0 ~ec- 0 0 . 0 0 100
b31.2 1.0 ~o~i~1.0 1~2 1.9 1.5
9 ~)11. 0 2, 5 necr. 0 0 0 0 100
. b)4.2 3.4 3J0 1,5 0.9 1.0 o~6 ~G
o 9.~ 11,5 ~2.3 7.1 5.~ ~.7 3.6 61
~,., "., , ,_.__A_.,. .. ~ .. .....
No ~ oxe` 1 6 17 17 i 7 q7 17 17 1 ~)r
tumor~
23 FEB '94 14:59 P.24
2 ~ 7 ~1
-- 19 --
~ble 6 ~cont~nued~
Rat ~Jo. Ini- ~t intervals o~ ~w~ck~ 7~ r~;
tlal 1 2 3 d, 5 6
~ze_ ~ ~ __ .. ~_
5 ~ ra~
ria~- 9.,~ 7.0 5.5 5~3 3.7 4~4 5~ w:l.t;h-
~on (1.0~ (0.~- (0- ~0- (0- (0- (0- out
ran 24.0) 29.6) 23.~ 19.2) 15.5) 22,7) 31.7) e~-
g~ 2 ) 1
~d t.urn,
~yt~r.- re .~;r.
ol,~m0an 3) 5
P ~oomp~ ~ ulith
r~ær.
rison
~rl"h ini- ~0~%
I;~al d~-t~) ;>0,05 ~0,05 <0.05 <0.01 ~0,01~0.01 (C-
II. Untr~t~d ~nlm.c~ls too~ltrol) _
~1.5 18.. 4 21~8 30.5 ~2.5 .~isd
2 . 9. 3 22,, 1 33 . 4died
3 12.5 13.3 18,1 21.0 2~'3.7 3B~3 died
4 12.0 19.2 30.5 42.8 50.8 59.~ died
9.5 15.~ 21.7 3g.2 43~6 di~d .- .
G ~ 3.4 5~4 a.2 ~.6 . 15c1
b) 5.6 7.0 8.9 10.0 .12,2 dlod
No~ ~
~umox~ 7 7 7 6 6 2
~JI (Yar~-
~,tion 9.1 14,,5 20,7 25,5 32.1
~) ~2.4) (5271) ~3624) (~2.6) 50.2~ ~.. ,... ~ ~-
P ~cor1pn--
ri30n ~Ji.'ch <0.05 ~0.05 <,o.os <o,o1~,0~01
itial
~ ;Jotc~ 'lhe~ 2-3 ~ or~ :Eusod ~nto one, th~ ~ati~tic~l -
~ree,tm~nt toolr 5 tltO a¢count 2 or 3 1;wnors-
2" ~Iho tumor ~ze equal to 0 (r~3x~s~on) wa~ con-
~id~rcd ~ one tuT~o~
,, ., . . .... ~
23 FE~ ' 94 15: 01 P ~ Z5
2~.6.~7li
- 20 -
5. In contr~t to other cyto~tatic dru~s, the alle-
ged pharmaceutical durin~ the ~roce~s o~ t~nor re~res3ion
can e;cert an anal~et~.c ~f~ct as w~ ~ollo~d in th~ ex-
periment~ signi~ic~nt incre~3e in th~ thre~ho~d of
the pain e~:citabilit~ and,co~equently, ~ d~cr~a~e in
tl~e pain sen3~ti~ity in ani.mal~, In the ab~ence of re~-
r~3ion th~ an~lgcti~ f'eot: o~ 1, and thi~3 m~.y b/3
used clinically ~or the evalu.~iion o~ the ef~ec~ o~ t~e-
rapy.
6. In contra~t to tha prototypo, ~h~ allo~d pharm~-
¢eutical may exert the ~ntibl~tic e~ec~ on the lon~
terr.l growing cancer ~umor3 partially or completely lo~-
ing their ~usceptibility to androgen~ which may be r-m
e~per~mcntal ~odel o~ cl~nicall~ n~slected c~lc~r pxoce~s.
15 In thi9 ca3e the antitumoral prepar~'~ion cont2ins, in
tur~ h D~-Yaline, ~1 ~n~bolic dru~ r,~eth~nclro~t~n:~
lone ana a k~o~m ~ntituberculo~i~ drug phthi~3~id ~',~ch
h~ preYiously never been u~ed as antitor.lul~al d~u~s. In
this ¢ompo~ltion, the new an~titumoral pr~p~tio~ exer~-
20 1~ the anti~la3tic e~ect on largn .u-qed (2-3~ Qnd tre-
mendous ~ingle ~:~erimentally induced tumorY (tlp to 2~, o
cm3) c~uses the re~re~3ion o~ the ~umor~ acco~p~nie~ ~y
xequent necro~e~. In this ca~a th~ liquid s~ructureles~
tumor m~e~ pora our, and healin~ o~ normal tissue~ '~;3-
~_ 25 gin~ at thi8 s~to ~ee ~ble 6
70 I.~orphological le~on3 ~ch OCC~ in ~h9 t1~no~
t~3ue ~nd rG3ult in rcgre~3i.0n al30 ha~ their peculi~r
f~atuxe~s unde~ thQ in~luence o~ th~ d ~a~in~ the~peu~ic
e~eo~ o~ any chcmloal dru~ and ~ven irradiation the~e
30 oocurs marked ~ibe~ ~ormation, wherea~ the ~lle~erl ph~
m~ceutical influce~ chan~e3 due rao3tly to the l~si~ o~ :
ths cell~ o~ p~rench~ra ~nd ~roma o~ t}le tu~..or ti~ue,
necroly~is with ~ub~equent re~orption (sae ~ig. 1~.
On t~e ba~is o~ ~h~ a~orementioned expeximent31 da~
and, a~pecially, taking into account complete harml~s~nos~
of t~P n~w antitumoral preparation teated and coniirmed
in nor~al anim~l~ within the ~rama~ork o~ the com~l~ted
~ .
Z3 FE~3 '54 15: 03
P.Z6
21~.6;~711
...... , . _._ _ _
_ 21 -
pharm2cob~010~;ic21 pre-clinics.l trial~ we propo~e îor cli-
nloal application a new a~t.itul~or~l pilarmaceutic~l con~
ting of a mechenical mi~c t~ ~ of 2 4 ~; o~ DI.-valine smirlo
Qcid and a low non-therapeu1;1c~1 do~e o.o~o-o.02s e meth~Jl-
testosteron~ per day ~or trea~nt o~ hormono-~u~ce~tible
cQncer tumor~ in women, ~nd a phar~ceut~c~l con~i~tin~
o~ a mechanloal ml~ture o~ 2-4 ~ o~ D~-v~line, 0.005-
0.010 ~ meth~ndro~tenolo~e an~ 0.~-0.5 g phthi~azid dai-
ly *or tr~at~ent of canc~r tumors wh~ch ha~e ~artially or
completel~ 109t their hor~none-susc3ptib~1ity,
~he dGily ~c3e3 o~ the propo~ed pharmaceutical for
clinical u~s h~ve beon calcul~t~d ~rom the do~e~ u~ed e:~-
p~rimental~y.
Thu~, the do~e for D~-~alir!~ ~a~ calculatad to be
2-4 ~ takin~ into accol~t the e~perimental do~a o~ 500-
550 m~ .bod~ ei~ht of anLmal~ and at l~a3t 10 timc~
lower intensity o~ arnino acid metaboli~m in man; con~equ-
~n~cly, a~ouv 50-55 mG~e~ body wei~ht o~ man oE D~-valine
~hould be u~ed or 2-4 g daily for a peraon ~Je~hi
50-70 ~^
~o doQos- o~ r, ~ t~::ro cl~laulut~d tn a di:EIerent
way, since human and ~nimal sen3it~ y to t`,~a~ que~'v
does r.ot corr late ~ith di~erence~ ~n the macabo~ ~stn
lnten~ity,
~_ 25 A do~e o~ mcthyltestosterone 20-25 m~ or 0.020-~025 -:
5 ta~let3) per day wa~ o~lculated on tha ba3i~ OL
e:cperimOntal ~nd ¢linical data acoordin~ to which ~t3
oxperi~.esltal nonther~peutic do~s ~5 r~v~k,¢ bod~r w~ ht)
~e 5 time~ lo~ than th~ th~rapeutio one - ~5 rr.g~ an~
~al body weight. ~ on~ take~ into account that nand-
rogen therap~ in clinic~l case~ o~ m~mmary ~la~ro ~pula-
te~ ~ dose o~ methylte~to3terone of 100 mg ~r.d more daily
~ee ~uakin, Ya,I1., in t~Hormone therapy o~ rna~nary ~land
cancer'~ .edi~in~" ~ubli~ers, ~,I., 1969, p. 6~-73), the
non-t;1c~apeutic do~e should bs about ~0-25 rn~ daily. Sin-
ce the dose o~ met'nGndro~nolone c~n~ot be calculated
o~nthe b~si~ o~ ~ens$ti~i~y to it o~ the tumor ti~sue be-
23 FE~ '94 15:05 P.Z7
.--`
. . _ . _ . . . _
- 22 -
cau~ it h~ ~evor been ussd a3 an ~tit~or~l d~u~, ~re
~de ou.~ c~lculation~ ~rom ths d~ta in the literatu~e
(See IlPhar~aceuLical~r, I,l.D, rla~h'.iov~y, ~I,Iedizi~a~ b-
lishers, r~,, 1985, pa~t l, p. 317; and dircct cli~ical
ob3e~vations in treating ~ol~eex~. It wa~ thus est~b-
li~hed that in ne~lected casc~ wi~h CoMplOte 1039 0~`
hormone ~u~ceptibility by the twmors it wa3 necessary
to u~e methanQro~l~enolone in a da~ly doso o~ 5-10 m~ in
co,~oinatlon ~th phthiYazid enh~ncing tl;~ col1ductive
e~`ect o~ thi~ hormo~c. ~or phthivazid the d~ly dOBe
c~lculat;ed ~:~om the experiiner.tal oIle with due con~ l-
ders,tion o~ 10-fold lo~r~r met~ooli~m inte~lty in ilumuns
_. ~3 compared ~ith ~r~all ms~nmal~ .. a dose ~or an e~peri-
mental ~imal ~ra~) wa~ 45-50 mg/lcg body wei,~r,ht, ~or m~
15 it would be 4.5-5 mgJ]~ bod~ ;ht, or ~c~r a person
.lei~.in~. 60-S0 k~ or mo~ it would b3 about 300-500 m~
~G. ;,-0. ~ ~ ) p~r d~y.
r';le st;udies oi:` tii~ antibl~ ic pt~op~rti~es o:E tll^
n~tr pharmac~ulic~l in the clinic, ~nliy i~ incur~bl~
20 ~rolu~teer paticnt~ yield~ the ~ollotrin~ data ~lgni~lc~
tl~,r dis l;i~gui~hin~, it fror:~ th~ prototype.
1~ r~ direct antiturnoral e~ ect o~ e propc3ed
ph~rm~ccutical in the ~'orm of a mechanical mixture o .:
~-valine Q~d a lo~,~r nontherap~utic~l do~e o~ methylte~to-
. 25 ~terone is att~3ted by the re~ults o~ c.~.tologi~l e.ca~l-
~~ nat~o~ of ~lr~tion ~p~clr~en3 ~ror.3 tho ca~-ity ol the
utorus ~ter ~dr,lini~tration o~' thi~ pha~n~c~utlc~l ln c~
3e~ O~ 9nOOarClllO~I~ O~ t~e ut~rus body in ~em~le ~ol~-
t~era ~ivon no ~peci~ic treatment in thc ~re-operat~.on
3Q pariod ~rit,n th~ e:~c~ption o~ ~-valine in combin~ion
~rit'r. a lo~r doae o~ T3ethylte~to~terone. In all 9 patisnl~
~hi3 treat~er.~ resulted in a ~i~n~'~lca~ reduc~ion o~ ~he
tumor, sizes a~ ~ell a~ c~s~tion o~ pai~ ar.d blood~ sec-
retion~. In ~piration ~peciTnens collec~ed fxorn ~ever~l
of ~h~se ~atients at dif~'erent inter~ (10 d~3, 2 we~
4 weeX3) we ~i`ound dy~trophic~lly alte~od ~deno¢~cino~n
cell~ ~,'it~ n~ican~ valuolction o~ ~hi~ cytopl~m ~
nuclei, "cor~ododl~ outline~ of'. ~ nuclei, 1~9i~ of ~O;~B
23 FEB '94 15;07 ~,Z~
2 ~
-- 23 --
r.uclei and me.r'~ed v~Lcuole d,~-stro~h;y (s2a ~
. In 1~e~7ec1;ed c~ei~ roco~ni~eul ~ corlpl~tel~ c~r-
~ble, ~di~inia'"r~ on o:~ the r.o-~r prap,~.rQtion ~3 a mictu~e
OI' DI--valin~ wit~ methylt~to~arona 03~ wi.,h mo.,'.q~Ld~;~o-
5 ~1;c~lololle ~lld phth~ v~id Y~e~ulteù il~ ni.~.~i.c~t I~7~olon-
gation o-~ tlle 3urvlv~1 time o~ th~ p~tient with 5at~ ac-
tiO~ f ~ul~j ac l;i~ condition ~qnd in ~o~e ca~cs ~ith ~he ot~-
j~ctive siltibl3st:lc ~ec1; - ~301ut~0n o~ ~h~ tumori~.
3. The action o~ t:~le ral,/ e;ltitumoral pllN:;~rllacoutlc
lO Ll.~3 earl~ a~ with~n th~ Iir~t 7-10 ds.ys comt~l~Jel~J elir~i-
nat~3(l t`ne pa'n ~drome e~n in t`~o~3c ca a3 l~h~re ~3tl Oll~
._ n~rcotica halped only ~Jlthill a limitad tir.~e, Ior i~ t~n-
ce in .ne~s,~lected CA3e~ ritll meta~ e.~ i~to bone~, ekcO
4. q`he actlon of the new ph~r.maceu~ical ~n ~1L~ CCU5~-
15 3~ t~eat~ent i~ X10-t 2ccompaxli~d b~J a~r S1nS o~ .;o~
ci ~,y tt.l~TllGd~ T;liC ~ o t~ n~u~ ,, vo.
5 . I;~ e co~ OL ~ t~ t t.lJi ti~ tll~3 n~ p7
ce~ttical~ "he ~tltumnr re~i~t~.~ crea~ed '3VG11 ;n i;l-
our~bl~3 p~ti~nts ag m~:ht3~tt3d b~r the improvecl~nt in tl
20 perip~lt r~l blood compositiion, ~;cic~llL g~ill, lclpro~d ~7)e~
tit~ cr~3a3ea r,~orkin~; c~- p~cit;y.
iflt~.~rL', ~tl~2n~ 0~ w pl~ t~u';.'c2'~
co~sist3 i~ tne pos~i'oilit~;r o it~ 3uccas~3~ul usi3 in Ollt-
pa7;:L~l.lt W~lrC~ liC~! collsl~tar~bly dlst,inrrui.~lAe,~3 ',l.o ne.;
25 ~harm~ceu~,ical ~'ro;~ the ina~or~t~J o~ e k~o~im o;~ ol;;~ler,~-
p~3ut1ca1 dru~ 3r'~ 3e~rere .~ide-s~îect~ . ~r.tl ~ er~3b~
r~quirir,~, ho~pl'.,~l co~ition~ for tlLei~ ~pplic~io~.
S:ido ;3f:~cJ,s
~scnu,~ o~ .c nL"r.1~tE~a1le~ o~ the .no~ pl~ ~2couJ.ic~15
30 th~.ro are r~o ~ r~ic~lt, comp~1c~,c10r s. 4 10n~ ~ 'uorr:~ ~u~
to 2 clnn~ ) admini3traliio~ o:E m~thy1iie~3tos "erone Ln lo~r
~!o~ 12y cau~3 ';t~ ' m.s~11f~3~,~qt10n3 oL ~r.t.rl1i~m ~`nic'r
rzpid1y d1sappear P~l"er met'1~r1t~,3 '~,o~terox1~ a~ 13t~, i cn
1~; ~ia^~n'~_n~l~d.
`~5 T~` ~he r.e~;J ph.~.rn~ceu~u~ca1 i~ adl~lnis',,~Y~ac~ XC9~ e
~o~nt3 and tho pro~.ein die'., i~ ~ot ob~er~d, J"ner~e ~a"r
. ..
~ .................
23 FE~3 '94 15:12 P.23
-- 24 ~
. . .
occur ~nsi~ icant nau~eQ, ~r0~33 0:~ app9tlte, 10~ 3 0~
welxht. ~hc~ ns o:E ~mino acld di.~bQlance di~3~ppoar
~ ';er l~oduc1;ion o~ uhe ~ ,r doso o:~` l)L-v~lln~ on~,
ob~erva~ce o~ 'l,he p~ot;~i~ dietv
Contraindic~tion~
1, Prac~eding an~ro~e:n tllerap~
Ir ~uch Cll'3eS Q lcl;l do3~ o..~ me ~l~"rl~e~tc3tero~ o:F'
~l~.o l~t, therap~r ~chedule ca,lmo~ real- se l.JI~ i'ec l; o:~
3)I.-~Llinc conduc~oir ln ths '~-.lCi" ti~sue c~ 3.
10 ~ t~ 3~uic ~ c~ r~! J;tl~i^a~ scl~¢dul~-
,, r.l~J;~ ros~onolon~ ~d p.tl~,l~vazid3 T;laJ~ ux,e~
2. q~fl ~e.~ 0~ r.~et~ a l~ .;s7 b~c~a
-~pld ~ lo11 oi 'I;U~10~.~ rl~v~ re,ClllJ~¢~ 11 tl~s
~t~113 o~ ',h~ lood ~C~3~31~ I?rO~lt~;r~ Jv~-~
1-~ b~ .n,~
3.. ~ iou~ ~0:ri.13 ~:~ a+,~ o.~ o .. o~ rb ~C~Jv
I~ ?..,U~ a~l d~mt~ t ~ Oc~ai~.3 ~vlt~ ~v~ vr~iGil u; X~ ~t3rl~u ~ 3-
r~tio;~a~ lnt~r~re~luio~l~ b^u~ Li1aC~LU.~L~S~ i~
s"~r~oclate~ l t.'2~ px'op~rty- 0;' 01'~3dOmillQI~ t~ 'J'~)O'~ t-~
2C ~?'' ~ lin~ ~r~ o ClC-~ (1 .o ~n~3 ~l~m~.r;~ u~ o:? '.,'.1'3 ~dUr
L~ . nc~t to t't~ tu~o~
. r~lore~orc the ~p~l'; "Q',.iOll o~ Lhe Y~ Xr.~aCeUtlC~
13 po~stblo only ~:,.tn;~ co~ le';,o .'ne~?.ii~.c" o~ .v~llO~
25 da~,ræ ~I;er ope;~2t;0n) ~nci ce~3at~ o~.~vh~ ,3t~ ta
25 co~:d~i!vion~ :3lood tr~.,n~t~u!vlon (e3~C~ lLi~r~lUl;v~P~ æO
. vr~nrl ~3:~Iec'., clo~ o th~i ol ~h~ o~
~,~?.l~ .L't~ S3C~ .h~r2:~ 1;}1~ ~n~;r~ v~ -;Oi.1. o~ i'!.t3
,,,l;a~ coll~ical ~.u,~ 1, b a ~llsco;~ tl~ cd .~or ~ t '.;.;c.
~ u~ 3 l~ a~ n~, t.:~ U~3 o:P ~ 3'i:~c~ a-`~ c'~-
30 1~ h~3 s~:Lt mcL.~ cll~ 3t be ~ol~l~cl~
5~ I~o o~ .r æ~:~;,l';ul.lo~ g~; ~ho~ . c;.
'~.Ju ~rltll J;~ i n~t p~ a~ lc~
., D~ ., t'l~ L~2~ J; ~irl~ J~ pl~ c~u~ '.cl~l
~v ~a v .o~ o:? c, 4LlC;. i}o.C~.Lo~ .u., (,0,;~ ,3, ~hy "o~
3 j ;~ . v.&~ ul~. u L~q~, hcl~o !~ o l ~ , c0,;~ ac r~c . ~
.
'
23 FEB 'g4 15:12 P 30
2 ~ 7 ,~
-- 2 5 -- _
~xample~
r''ilC ln~nt. o~ U.'3'1;'L',o'',~?tl b;y I;1Le "ollowinG ~pcci-
~ic ~.nmt~le s o~ th~ mo~al t~ o~erJ;.ie~ o~ ~h~ allcged
new pha~maccutic,71
1. Pa'~ion~ 37r.il~0v.3~ A. 75 ~ r~ ol~, ca~c his-
to~y ~o, 127~3~a. i3.r,~70~E~to~ ~roto;~-~r WEl:3 C~O`lC o:
31. 05~1977 ~t; the g~ colo~ departt.~ lt; o f ~o~to~r R~ e~
~rch Institu~e ol` oncolo~ L me~as4~sis f~om ~,hc ~;r~3a-
t~3r omentum w~ tal;en ~o~ hi~tologic.al Q~lal~r~is Mo.,
10 104~47-~343- Clandul~r ~ol~.d. o~ra~?~r cnn~or
Clinical cliagnosl~: o~rary crncer Of ~ a~ i. I;h
i1tv~ e t.ulnor $row1;1~ arld oul;,oro~.rtn i~to th~ in'.,~E tilte~,
with Ir.et~lta~3~3 into the omentv.m and in the livar, ~ith
~citic ~luid accu~ulation in lh~ ~domin~l c~vit~r.
In th~ ~o,st~oper~tio.ll perlol, ~ cou~e o~ c~te.no-
th~rapy (i~ thio_t~pQ) ~s~ v~n aa ~ rc.~ult o l,ih:ich
no s.acito3 ~ccwnu~te~1 ~ut th~ ~umox ~ro~rl;h cont~ m
In ~uly, thc p~tient ~sa~ dl~chax~e~ ~rotn th~ ho~
~td pre~crlbad 3ytnptom~tic. trentrn~nt.
In lal;~3 July, 1977, a~ a voluntc~r, khc pavi~
welænin~; 5~ 3~;, be~an tho tr~tment ~,rlth t~1~ pro~e;3~l
ph~rmac~utic~l ln t'n~ ~orm o~ ~: mixtur~ o:~ 2 ~ DL~ re
ill combin~l~,ioxl Wi1;h 25 ~lg ~0.025 ~;) or 5. tab~ r~l~3~}i;irl-
1t,0~ t~.ront3 per d~J, ~it`~ ~trict o'~ .r.ce o.i` t`tle
2 5 m~ with ~..hc c~iYi~ion o~` the d~ily do~e :3 nto ~ 3inr;1
~ ,.. . . .
ono~i l;a'.sen b~:~or~ ; 0.5 ~ D~-v~lin~ q~rr:~ m:l;1: en-
tarall~J and 1 t~blot o:E i~ethyl~ 1;osterorle subl:in~ ,lly
~l. I;imt3~, arld 1 liubl~u o~ rnt3t,h~rl1;e~to~3'.~ n~i ~ublinr,u~lly
r~ nicldl~ ;ho d~ itho~l~; DI~v~l~n~. 'I.'}1~3 t~ur~tlon
~0 o ~` t}~e cour~i e - 2 mon l;hs .
Dv~inf~ thi.~ t:i sr.~ 1;h~? pai:n~3 in 1 e lo~ b~orn~n nr~d
ilL th~ r.x~E3 o~ t~ c~s~l ccr;sple~cl~, th~ ~7aSI~.~.'O-
illt:e.~liinal trs.ct furction ~o~m~liz~d ~con~tipaLion~
l:)lood~- ~ecxatic~3 di~ e.re~.), the ~etl.te is~pro~re~,
wei,~h~ r~ 4~5 }c~, the ~tre~l~th ~ld ~ror1cln~ capa
C ~ wexe r~toxed, ~o t~ mor waa palp~ted.
O~rlng to thi~ 5tnt;l~s the p~lU-~ ~nt; ~ 3 ho~pitall~ecl.
23 FEB '9~ 15:14 P.~ll
2 ~ 3. ~ ~ 7 ~
..... __ . 2 6
on~ month l~ter for the 2nd coWr~3Q OI chemothcrap~r (im,
thio-t~pa, a total do~s o~ 200 m~), G~ecolo~ical ax~mi_
nations ~e-u e~l~3d no n~opl~ia,
In ~ ch ~d Ju~y, 1973, propllylQctically ~ ~ore cour-
5 8c~3 oi~ thio-tepQ wero ,jiven which pro~uco~ ~tabl~ leuko-
pen:La,
In ~u~;us t, 1 Y78 a ~acond cour.qo o~` the pxop~d phar-
maceut:i cal ~raa ~ive~ by thc ~arle 3ch~dul~ ~o~ 1 ~ontih~ 5~he
blood ar~l~r3is ~ no;~m.~l. On the 7th da,.,~ o~ tll~ trcatl~e~lt
10 ~hc pati2nt hafl severe pairl~ in the liver a~ea Y~hich pe~-
,t~a :E or 2~ h.ours but then dis~ppc~red compl~ r. ~yn~-
~olo ~i c~l ~xal~inat ion rc voalad ~o ~loopl~ h~ pat i~nt
~elt w~ll. No ~r~atm~3nt ~s ~;iVOn unl;il April next ~e~r
gener2l c~ndit;ion was satls~aciiory, ~aineû soms v~ t,
15 ~mecolo~;lce.l ~:~nin~tion~ Y~e~r~ale~l nothin~s.
In late April-r.lay, ~979, ~he Yl~S ~iverl a 5th (})~c~hy
lflctlc) courr~3 of 1;hio--i.opa, im~, toler~ted ~3a'l,1'3~ ,ct;ox'i.-
ly.
Tn .June, 1979, ~}la W3~3 gi~ren a 3rd ~proph,yl~ctio ) c~i-
20 u~ o~ the n~w phQrm~.ceutic~l but ir.~ ancther daily do~eb~caus~ o~ Lc~lt chantro o~ wai~;ht in 2 l,r~r~
~:EroTl 54 kg to ~a k~ hc ,~;aine~l 14 k,~;~r Sh~ we.
re2l 3 ~ Ct~re o~ 3 ~ ine a~ 25 ~ er~lylte~ n~
dall~r in 4 ~in~ do~cs, ~ri.th th~3 c~ne (lie.'. r,h~ cotlr~3e
~5 l~t~ 2 month~3. ~h~rs a~p~re~ 3$,~,n~ic~.1; 3i~3 ~
~_ virillty ~rhich opprec~c~l t;he p~tiCll~ b~cau:~e o~ l:lb~,do
m~li~e~ tatio2i3, :3ec~qe o~ th:L,q, ,s~.e d~cli~cd ~ur';hcr
pro~hy~ao1iic admi~i~ l;rQtion o:l~ the n~w p~rTn~cauti¢al~ ~a-
~it7 in 1979, i:~ ~pxin~ d ~UtUt~l 0~ 1980 she w~ iv~n 3
3t~ l~O~C pl~)ph~ c ~G.~C c~ u:",~ ,r ch~v~r.ctllfl~y ~ri lih cyclollo.~v-
phar,o ~hio~ ~he toleral;ed Wi-Gh mor~3 di~'~iculty,
n ~a~rtl~r~r ~~ rar~.h 1~1~1 the ~2ti~vnt ~SU~L:er~ ;ro
ults. S~e d~erl r,,~tll the 3econa, ~itho~ ny ~ o~
noopl~si~ w]rtvh ~ad ~t~n c~l;abli~h~d, ~t a ~ 0lo~ic~
35 c~ in~tion on-~ Ir.oTlth 1~vfo-la d~nt.l~ he re:!.avive~ r~fus~d
th~ alltop,sy.
r~h-- ocn~.lu~3lon 9~. incre,n~c ln ~ht) perio~l of ~cti.~re
li~e hy 4 ~ear~ a~tt~r recognition o~ ker cor:ditiorl ,c~
: .' ' - '~ ,;: ' ' :~ '' : ''', . ' '' ~: ~ '' ~ ' ' '~ ~ . . :
`'` ,,,, ::'.'' '' ' ' :' ,~ '.. '.. ,,.. . .. ~; .. ' .. ,. ' ','', " . ;: ,.. ..
23 FEB ' 94 15: 16 P . :32
:. ,
27
. c~o~plQt~ly l~c~urnble cnnn~t b~3 r~8~rdGd t~ b~ dll~ to th~
~3ucce~s Or t~a~ltlonal c~ncer chem~t~apy ~1~ e rl~7w .
pharmaceut~oal not only correct~d ths ~ida o~f00t~ o~
c}lemical drug9 but cle~rly ~aoilitat2d the ~ntiblQ~tic
5 e~fect~
2. Patien1; Tlc~henko , lq.A., 28 ycars old , ca~e hi~-
~or~r No. 1151a~x, admittoc~ to ~ynecolo~ical departm~t o~
Ros-tov R~sear¢h In~ti'~uto of oncolo~ .0~ Tllo ~ta~
tu~ at ad~ ion: wi~hin 2 month~ e~eat ~rllar~s~3ment o~
10 the abdomen, ~;re~t ~ei~;hli los~, evenin~ tcmpcr~t~ out
39C, ~3u~ 0c~tl0n, X-r~,y o~' the che~t ~eveQlad a met,a-
st~is lnto ine pulmon~ y pleura. ~:ndol~ilphat~c polycho-
`~ mother~py ~va~ ~tarted bllt did not allev~at~ th~ condit~on
o~ '"he patl~nt.
1~ ~n 31.,08.~9 a~ explor~tory l~p~ro~omy r~a~ per~ox~ d
wi'l,}l a~acuation OI 15 1 o.~ asci~lc ~'lu~ ~ro~ the ~ lo-
;ni ~ c~vit~r ar.d ~,he al)out 2 lit~c~ o~ :Elu~ d i~2~0m tj}
pleu~al c~ityv
"~ha dia~no~ oY~ry c~nca~ o~ IV ~t~g~ lrrit~ oU'L-
20 growt}l o* the twnor~ lnto tha ~nte~tina~ ~nd with mct~ta-
o~ into the gr l;e:r ornantum, liver, paritonow~ pleura~met~ t~o plcurit~). Hi~tolo~l¢al an~lysi~ ~o~ 26~62s
! ~l~ndul~r-o~pi~lary canoe~. ,
On 13.09.89 a preparation o~.platinum ~B~ inoo~lated
intr~pe~itone~lly. ~ter ~hl~ th~ condition o~ t~e p~-
ti~nt d3texIorated e~e~ more, she Y~a~ conside~ed to ba in-
cuxabl~ and ~ di~oh~r~d ~rom th~ ho~pital in the ~re-
terminal oondition~ :
On ~6.09.ag ohe be~n, ~ ol~teer, the treatment
~th the n~7 pharmaceutical in the outpat~ent department~
Ths daily do~e ~th the pati~nt'~ wei~ht a~out 70 k~)
consisted o~ 3 ~ aline in combination ~th 25 mg
O.025 ~ or 5 tablets) methylte~tosterone. The daile do-
line F~ublin~u~llg 2 time~ i~ the mlddle o~ tha d3y ~e70
-
Z3 FEE3 ' 94 15: 18 P . 33
2 ~
moal~ he pat~ent ~trictly obæerved the dlet wlth thc
exce~3 o~ protein, liTTited amount o~ caxbohydxat~ and
complet~ ~x¢lu~ion o~ ~mal ~at and phosphol~pid~ ish
hard~roo, e~;g yolk), u~in~" no ~ore Jchs~ 1-2 1;able ipoon-
5 ~ul~ o~ ~regetable oil daily.
~ '~thin the ~irst 10-15 d~y~ o~ treatmen~ with ',he
new pha~maceutical the ~ollov/~n~ ch~nge~ occured 1~1 the
condltio~; o~ ,.he pal;ient s
1. Vomit;in~ ~topped and lnt~s~inal oY~cuQ~lon OOCIIr-
10 red indep~ndently;
2. ~he body ~empe~aturc beca~e noxlln~l;
3~ e ur~ no oolour ~c~ne li~hter ~pre~ioll~J.y _
dar~c beer ~olour);
~ r~ ~0 ækin coloux ohan~ed from dra~-green illtO ye7-
15 l~ Yhi te.
5, ~h~ er ~nl~r~ed ~ htly ~nd pexiodia311y ~Ta~
pairlLul;
6. sn'nyc~.~dia Qppe~red ~ro~ ~ime to t~r~lC~;
7. ~e ~atiant ~howed ~ood ~pp~tite:~nd intore~t ~or
li~e,
e cour,q~ o~ 1:reatment ~va3 1 ~onth becau~ the pa~ :
~ient ~va~ con~idered to be cur~bla ~nd w~ ~r~clltl~ ho~pi-
taliæ~d o~ 23,10~9 ~or a repoated i~txaper~ton~ ac- .
tion o~ ~latinu~ prep~x~tion~ he patlen~ bo~e the in3~c-
tion o~ th~ pl~Jcir.u~ preparation eaaior than th~ ~ir~
time~ but th~rea~aln appe~r~d ain~s o~ cardio-pulmon~y - .
in~u~c~nc~
A~ter tlae diachar~e from th~ ho~pitQ1~ on 09~11.89
tho pa~ient ~g~in 1~e~n to ~t th~ tre~t~iarl~ w~t}l the ne~
ph~rln~outlcal, ~ 2~month cou~ o~mbe~-D~cemb~r, 19~9)~
ChQnge~ i~ thi~ p~riod: ~
1. Sigr~ o~ c~rdio-pulmonnr~ insu~f~ciency dl~ppe-
ar~d.
2~ Pexio~lc~lly oc~urir~ p~ in tne liver ~topped ~-
but the live-r Yla3 3till onl~ed~
3. ~o s~ gn~ o~ aaoite~ eith~r in th~ abdolnial~l or
in pleur~l cQvi~y.
~ 'he ~ppe~lJ~e ~ 3~il-l ~ood, ~aln in '~7~ 4 k~
:~
23 FEE3 ' 94 15: 20 ~ . 34
i 7 ~
2 ~
5. ~h~ patient t~ko~ ac~ive pa:rt ~n liîe, w~nt~ to
go to uork but she get~ ti~ed quic'cly~
I~l J~nu~ry 199~, she ~IQ~ ho~pitnlizec~ ~or 3 w~k-co-
ur~e of ~y~temic chemotilerQpy ~im, thio-1;o~ u~ich wa~
5 tol~rat~cl ~ti~r~Cto~ly, without diso:rd.er~ hc-modyna-
, wlthou~ nau~c~ ~d vomitlng, Bu~; the cour~s ~a3 notcorlpl~ ~.ed arld di~¢ontin~l~d b~c~u~e o~ .~ se~rs sllcrgia
ede~na o~ ~u~cke'~ tgp~ t t;hi~ time ~?ai~ in t~ ight
~nd le~t h~ochondrium.
Earl~ 'ebru~ry, ~990 ~ tt,t~o-month COU'n'~2 (,~ l'U
ary~ arch) o~ ~;re~tment w:ith t;he new pharrJI~oeutioal Y~S
st~rted in ~hc Sam9 dose~ cs before. A~t~r the cour~s:
1. ~he ob~octiv~ ~t~tu~: a~ ~ho~rn~ by ~ ologic~1
ex~;nin~ti~n, ln the ~mQll pelvi~ ~ll tunoral ~ormatio~3
15 w:th the e~cceptio~ of ~, ~mall tWllOX on the ri~ht ~lde
~Q:~` the ~ e o~ ~ child ~ t ) rc~olve~; no ~i~ n~ o~
mot~Qtic ~?lsuritis.
2. q~he ~ub~ ective ~tatus i~ gOoa. Plan.s to ~e1i ~.ar-
riodO Early .in April sh~ ~Y~ rnal~ried; reIu~ed a~ny ~x~a,t-
20 m~nt ~or ~pril ~n~ ~IQ~ ense~ ~b~ent for ~ mcnu':s ~t~--
te~d on I,t.~y 1.
In the mid-~ay, 1990, h~ e~e~,:the~ ppe~od 3i~n~ .
o~ metn~t~tic pleurit~: hard bl~cathillg, ~luid l~ t~o l~t.
~_ lu~ up ~o t~e 3xd ~ Cllan~e9 ~2i th0 ~all p~ v
~om ~3~ 18, 1990, shs Yra~ ~iYon a.cours~ o~ s~t~
mic ch~motherapy with c~cloplio~hane ~ n ~n . ~utpP tient w~rd
w~th no result: pleuritl~ progre~ d ~'luid up to the 5th
rib~, .
on Jlme 4, 1~0, the ~*h co~ O~ til~3xa~ th the
3 ne~ pharmaceutl~ l W~3 ~rted wlth a dail~ dose of D~
line 3 ~ Qnd. mct.hylt~tc3te~0ne 3 ta~lo~ .()15 g), b~cau-
the patient, duo to a very hi3h l~bido, re~u~d to take
5 tablet~ pet~ dn~ (0,0.25 g), int~r~ g ot~er~ 3e ~o di~con-
t~r.u~ any therapy~ I~ 2 week~ o~ the J,ire~tme~ pleuri~
decrea~e~ n to th~ 3~d ri~), re,Q~ir~tior, b~camo ~-
~ier.
~ y th~ l~c~u~e~ o.~ ~he physici~n-~n-char~, chc~otile-
23 FEEI ' 94 15: 2;~ P . 35
~ 2 ~ 7 ~1
. . .
rapy ~th cyclopho~phQne (2 wo~k~) was ~ltexnated ~th
the treatment u~in~ the ne~r pharm~ceutical t2 week~),
~ter t~Yo suoh alternation~ the patient refu~ed to ta~e
more chemotherapy v~th cyclopho~ph~ne because each time
it cau~ed very ~trong aller~ic edema o~ pude~dal lip~
a~d l~r~nx not ~110Y~ at~d by t~lo n~t~r pl~rm~o~u tloal.
¦ For ~ year ~Au~ust, 1990 ~ Au~u9t, 1991) the p~tient
carried out ind~pendent treatment ~Yith the new ph~maceuD
tical in oourse~ o~ 1-2 months i~ the sQme do~es w~th
approæ~m~tely one-month inter~als, However, the ~enerQli-
z~tion of the pro¢es~ continued slowly: there ~ppeQred ~ :
a meta~ta~i~ in tl1e le~t brea~t, in the i~t~rpleural
area there a¢cumulated the ~luid which in thi~ period
w~s removed 3 time~
S~nce it appeared de~inite that mnlignant neopla-
~ia9 by the end of that year ~illing the ~mall pelvi~
h~d complotely lo~t ~uscept~billty to hormono~ ,on Au~ ust
13, 1991, the treatment with the m~chQnical mlxturc ~a~
startod: 3 ~ o~ D~ linc, 0.005 g meth~ndro3tenolone, : :
and 0.3 ~ phthi~azid per day, All t~l~ mixture ~Ya3 ~
ded into 2 sin$1e dose~ in the morn~n~ ~nd the evening;
eQch con~i~ting o~ 1.5 ~ Dl-valine ~nd 1~2 tablet methen- :
dro~tenolone, 1/2 tablet phthi~azid ~ith warm milk on an
ampty ~tom~cll~ ~ cour~e o~ 1 month. . `:
_, 25 ~hl3 treat~ent app~rently cau~ed oxtensive necrotic
generation of meta~ta~es in the i~terpleural cavity: the
temperatuxe rOSQ ~ig~ by the e~enin$, se~are coughing
deYeloped, hard breathinB. Vomiting occurred onco in 1-~
da~r~ ~ th~ Yomitu~ containln6 dark 3truoturele~ masse~
a~ter th~ the iever dropped~ breathin~ b~came ea~iar,
but coughing did not ~top.
~r the p~tient 13 raquest is sep~ember 1991 9he WQ9
q again gi~en a 1-month cour~e o~ treatment ~th D1-~allne
~ (3 g~) in combinatlon ~th 0,015 g methyltestosterone.
j~ 35 Cou~hing ~lightly decrea~ed, ~omiting ~topp~d, hoY~er,
~ the ~el1eraliæ~tion of the proCe39 con'i~ued: the metas-
j t~is in the bre~t bc~n to grow out into t'ne back mu~-
cl es .
~j .
~ ~cl: ~4 1~i~4 P.3ti
2 ~ 7 ~1
~ arl~ in octob~r another course ~as started with a
mixture o~ D~-valine, methandrostenolone ~nd phthivazid
in the ~ e dose~ e couEhing incr~ased, ~requen~ epl-
~ode~ o~ su~ocat~on de~eloped,a.ttempts at the ~luld
pump~ng out showed the absencc o~ the latters apparentltr .
the cavity ~ra~ ~illed with tumor ma~se~. Cardiac weak-
nes~ increased. No paln~. ~he patient ~ldom le~t the
house because Or dif~lculties in climblng the ~tairs,
but at home she read, ~Yrote, ~reely ~o~ed about the room.
On ~ovember 8, 1991 the patient dled of a heart
Qttack ~or 30-40 mln, She had lived mo~e than 2 ye~
~rom the time she had baen con~idered to be i~curable.
The conclu~ions
~ e succe~ in prolon~ation of the acti~e li~e
~ thi~ youn~ woman c~nnot be as~ociated with the treat-
~ent ~ith the new phar~aoeutical elone because in the
19~ year she receivad the con~entional chemotherap~t cour-
~e~ ~rhich ~he coul~ hardl~ tolerate each time.
2, ~he turning point towards tlle n~w ~eneralization
~ the process fell on April-~.lay when all the traatme~t
~28 dis~ontinued. ~hi~ ~hould no~ ha~a been done. Slnce
our treatment t~as onl~ YoluntarJ w~ had no rl~ht to in-
~i~t.
. . . 3~ ~h~ u~e o~ the miæture o~ D~-vallne, methanaro- 2~ stonolone and phthi~azld, in our oplnlon, ~'rQ~ too delay-
ed ~nd the time had probably been 105t ~or it~ optimal
- e~fect.
~ he new pharmac~utlcal v~th the antitumoral activity
in th~ ~or o~ ~ mixture o~ DIr~al~ne and ~mall doses of
3o methylte~to~terone ~!~a3 lnit~all~ tried ~n 33 patient~
(volunteer~) t~th malignant tumor~ of genitalia con~ir-
med hi~tologicall~ as cancer of the ~ollo~Jin~ localiza-
tion~: ~ali~nant ovar~ cancer~ - 9 patients, malignant
tumor9 o~ the uterus bod~ - 21 patient~, cance~ o~ the
uterine tube - one patient, cervical cancer - 2 patient~.
~ ith the sxeption of 9 patient~ ~lith the uteru~
~od~ c~ncer in the II~ tage o~ the d-lsea3e ~o~
23 FE~ '94 15:27 P.~37
2 ~
_ _ _
- 32 -
the ne~ ~harmaceut~cal wa~ u~ed a~ the fir3t ~tase of
tre~tlten~ ln the pre;operation pe~iod, all the ot~cr pa-
tients wore in the III-IV ~ta~e o~ the disea~e a~d ~y
the time o~ treatment ~rith th3 new pharmaceutic they had
been given the convention~l tre~tment or chomoth~rapy
alone, ~thout ~ny o~ect, having larg~ immovable tumor
ccn~lomerates in the ~mall pelvi9 oe esudate3 into ~2-
riou~ ca~ities, ~ome o~ them had xelap~es of th~ di3e~ise
a~ter ine~fective combinea treatment.
~i~.o~t o~ tho p~tient~ treated ~!~th the new pharDtaceu-
tical a good (tumor~ re~olved) or ~Qti~f~¢tory e~ec~
Complete lack o~ e~ect w~ ob3erved i5 5 p~tients only.
ln ~our of th~m the tumor~ w~re de~ln~tely ho~to~e-un3us-
coptible: cervical c~ncer, uterine tube cancer, sarcoma
15 On the uteru~ body, and the ~th patient wQs pre~ented
~or tre~tme~t in a ~ery ~e~re o~ndit~oll du~ to r~p~d
~enerallzation o~ the proce~s.
~ he propo~ed pharmaceutical wa3 al30 tested in 5
incurable p2tients suf~exin~ ~rom tha mammPry gl~nd can-
.~ 20 ¢~r ~th metast~es into bo~e3, ~th groi~n~ out meta~ta-
j se~ int;o the s~u~cles o~ in o~ the chest t~/ho were dis-
ch~rged for ~ ptomatic treatment in a vér~ ~evare condi-
tlon a~er ine~cti~e irrad~at,$on therap~ and 10-12 cour-
se~ o~ chemotherapy~
`~ 25 In one o~ these o~e,q, a~ter a long-term hospital
. treatment ~t~3tases lnto the bon~ o~ ~e slmll~ pol~
ribs led to the pre-terminQl condition.o~ the patient
I and ~ha was brought ~rom the ho3pital on tha stretoher~.
~h~ o~ct o~ th~ tre~tment witll th~ me¢hanical mixt,ura
30 o~ 2 g DIrvaline and 20 m~ metl1ylte~to~qt~rone w~3 both
~ubJRcti~e and ob~¢ti~e. S~e~est pains usuall~ accompa-
nyin~ ~uch meta3ta3isin~ which coild only ba ~topp~d
~or 11/2-2 hour~ b~ trimep~ridine h~drochloride tpromedol3,
be~Qn to ~ub~ide ~nce the 3rd day of treatment and co~-
1 3~ pletel~ di~appeared w~thin 2 weelc~. A~ ~ r~ult, ~ a
! month the patient started to get up fro~ the bed Qnd
~ru~u~lly b~c~ms invol~ed i~ th~ ~cti~e life. Ever~ 2
month~, the ~ected par~,~ o~ the ~keleton were ex~.lined
~1
1-.~
~ 33 -
by roentgen, Si~ns o~ beginning reparation o~ th~ bone
ti3~ue were observed ~n ~kull end pel~l~ bone9. ~7ith ~hort
interr~l3 o~ 1-1'k weeks the p~tient too~ thc treatment in
the outpctient ~ d ~Ol' 8 ~onth~, unt~l she d~ed o~ throm-
boemboli~m ag a reeult o~ lon~-term uncontrolled taking
o~ calcium chloride for 3 months,
~ ntil the la3t day thi~ pQtient actl~aly did the
house wor~, went shoppin~ ~ld to th~ ma~l~etl
In 3 cases, t~eatmsnt with the mechan~cal mixture of
lo D~valina, methQndro~tenolon3 and phthivazid resulted in
temporary but well ~arl;ed sub~ectiva imp~o~ement in ~he
oondition o~ the patients which finally ended a~er an-
- other course o~ chemo~herapy b~c~use they were a~ai~
hospotalized into ohemo-ho~mone therapy department o~`
Ro~tov ~es~arch In~titu'e o~ Oncolo.~y.
In one oa~e, ~uch ~ub~ective considerable i~npro~e-
ment s topped sharpl~ durin~, the trea "ment with the pro-
po~ed pharmaceutical beca,u3e o~ tha ~,res~ condition o~
the patient de~reloping due to her personal problem~, She
20 ~la~ not hospltali~ed.
q~lle observationa c~L~ried out b~r the author ~ho~ed
the trea~nt ~rith t~le propo~ed phnrmE~cauti¢al t;o ~ re
mQinly s~tia~actory r~sult~ e~en e.~,er prevlously per~or-
~ed ine~octiYe chemo~-radlation therapy.
llhe tec~nical re~ult o~' th~ in~relltion con~ s in
the ~ollo~ ing.
I`he phar;nacoloeical properti~s o~ the propo~od
pharm3.cautical ~tudied e:cporimentall~r ~n i~duoed hori~ono-
~iusceptible tumor~ o~ mamn~r canc~r in ~ antl in nor-
30 mal animals, a~ well QS the dat~ obtained clinic~ in
treatlttent OI ~rolunteer~ in incur~l~ case~ atte~t to i~9
co~nplete harJ;tle~ne~s, sufficl~ntly t~tar~:ed ant,lblas~lc
prop~rtie~ with simultanaou~ s~imulation of the defence
foroos of the bod~r ~d an~1~et1c effect.
.,~
~ r~ 4 l~:Jl P~39
7 ~ ~ :
:
34 ~
A P~A~CEU~ICAL E~R~ING AN~ ORA~ AC~ Y ~: -
~gend~ for Pl~ures
Pi~ D~,~A-i~duc~d ma~m~xy glQnd cancsr in x~t~ :
1. Control - glandular-sol~d can¢er o~ th~ ma~mary
gland in rQt (untre~t~d). Ma~ni~i¢at-
ion x 160.
2. ~cpe~imont - a~ter tre~tment ~it~ D~-valino in
mlxture witl1 m~thylte~to~terons ~reg- -~
re3sion). I,larlced dy~trophic le~ioi1s ~ ~
in tumox oells: predomi~ant ~aouola-
tion o~ the cytopl~m and ly9i~ 0
both nucleu~ end ¢ytopla~m. i.~gni-
~ic~tio~ x 200,
~ig. 2 - Adcnoc~rcinoma o~ hum~n uterine body.
~pir~tion ~rom the uterin~ cavity tcytolo~y)
1~ ~s~ore ~reatm~nt. Ro~ette ~truoture~ from elon-
gatsd a typical c~119 0~ the c~ dor ~hap~
(magnific~tion ~ 600, im.).
2.. ~ra~me;1t ~or 2.weeks ~ith D~-valin~ and me~hyl-
te~to~terone~.~acuolation o~ th~ cytopla~m and
nuolei o~ t~moi- c~ell~ ~mn~ni~lc~t:Lon :1~600, lm)
3~ ~e~4m3n4 for 4 v~eeL~ vri'Gh DI~Yalin-3 and methyi~-
t~s~nf~t:erono~ J~la~kod ~3broh~r;o~ ;u~le~s fu-
- ~on o~ ~mall ~a~uole~ ln cytop~m ~nd nucle~
o~ tumor cell~ (m~gni~ication ~,6,p,o, im.). .
4~ ~rea~me~t ~or 10 day3~ A ~ayer oi d~stroph~callg
chan~d cancer cellss l~oorrodod" outl~s o~ the
nucl~, ly~ o~ individual nuolel (ma~n~c~-
tiOl~ X 60o, lm.).
. . .
