Ukrainian Anti-Cancer Institute2

TheEffectontheHeatShockProteins

InthetestswithhumanlymphomacellstheeffectofNSC631570onthelinesUͲ937and
UͲ937/hsp70wasdeterminated.Thesecelllinesdifferintheexpressionoftheheatshock
protein 70 (Hsp70). The line UͲ937/hsp70 turned out to be more resistant against the
effectofNSC631570.TheauthorsattributethistotheprotectiveeffectofHsp70(200).

TheEffectontheElectrokineticPotential

AstudyexaminedhowNSC631570affectstheelectrokinetic(EKP)potentialofmalignant
andbenigncells.TheEKPoftheEhrlich’scarcinomacellsdroppedafterincubationwith
NSC631570.TheEKPdecreaseofnormalcellswaslesspronounced(221).

THEINVIVOSTUDIES

The anticancer effect of the intravenous administration of NSC 631570 (4 µg/day) was
demonstrated in the tests on BALB/c mice with the implanted rapidly proliferating
mammary adenocarcinoma D1 DMBAͲ3. Three routes of administration were employed
for NSC 631570, e.g. intravenous, intraperitoneal and subcutaneous. Intravenous
administration was proven to be the most effective and inhibited the tumor growth
significantly.TheauthorsevaluatedalsotheroleofimmunefactorsintheeffectofNSC
631570andrevealedthisagentcanrestorethecytotoxiceffectofmacrophages(26,43).

LaterthismodeofactionwasconfirmedinastudyonCBAmice.Onceagaintheroleof
macrophagesintheantitumoreffectofNSC631570wasstressedbytheauthorsofthe
study(120).

InanexperimentalstudyNSC631570inhibitedthegrowthoftheprimarymelanomaBͲ16
anditsmetastasesinmice(107).

InthetestswithmiceC57BL6NSC631570inhibitedthegrowthandmetastazingofthe
primaryimplantedLewis’carcinomacomparedtothecontrolgroup(219).Thiseffectof
NSC 631570 was confirmed in another study. Here too, the intravenous administration
wasthemosteffective(254).

Inastudyon18miceCBA,themixtureof0.1mgNSC631570and10000carcinomacells
KrebsͲ2wasinjectedintramuscularly.Inthecontrolgrouponlytumorcellswereinjected.After
11daysasignificantinhibitionofthetumorgrowthwasestablishedinthegrouptreatedwith
NSC631570.Similareffectwasachievedalsoinmicewithimplantedhepatomacells(118).

In mice with implanted hepatoma HAͲ1, NSC 631570 increased the concentration of
procathepsin B in the ascitic fluid whereas the concentration of cathepsin B decreased.
Moreover,theconcentrationofthemacrophagealpͲhexosaminidaseincreased.Thisindicates
aninflowofmacrophagesintotheperitoneum(119).
39

The anticancer effect of NSC 631570 was also confirmed on Wistar rats with implanted
sarcomaͲ45(122).

TwodifferentformsofEhrlich’scarcinomacellsweretransplantedintraperitoneallyand
subcutaneouslytomice.NSC631570wasadministeredintraperitoneallyforsixdays.The
effect of the drug on the tumors was estimated by the indexes of the tumor growth
inhibition(TGI),totalnumberoftumorcellsinasciticfluid,numberofviabletumorcells
andaveragelifespanofexperimentalanimals.Cellcycledistributionofcancercellswas
determinedbyflowcytometry.Thenumberof circulatingphagocyteswasestimatedby
flow cytometry using FITCͲlabelled S. aureus. Intraperitoneal administration of NSC
631570 in mice with ascitic form of Ehrlich’s carcinoma resulted in moderate tumor
growth inhibition, but was accompanied by acute local inflammation and caused
reduction of life span of experimental animals. In the mice bearing the solid variant of
Ehrlich’s carcinoma the treatment with NSC 631570 led to significant TGI and slight
increase of life span. The treatment caused restitution of the number of circulating
phagocytesinperipheralbloodinthebothgroupsofanimals.Theauthorsconcludedthe
antitumoreffectofNSC631570wasmediatedbyitsdirectproapoptoticactionaswellas
bytheinteractionswiththemurineimmunecompetentcells(262).

TheEffectontheGrowthofMelanomaB16inMice

The effect of NSCͲ631570 alone or in combination with pathogenͲassociated molecules
(PAM)onthegrowthoflowͲandhighͲmetastasizingmelanomaB16inmicewasstudied.
NSCͲ631570wasadministeredintravenouslyandPAMintramuscularlytotumorͲbearing
miceseventimeseverythirdday,startingfromtheseconddayafterthetransplantation
oftumorcells.Theeffectofmonotherapyandcombinedtherapyontumorgrowthwas
evaluated by the indices of tumor growth inhibition in experimental animals. Cell cycle
distributionofcancercellswasdeterminedbyflowcytometry.TAP1andTAP2expression
wasevaluatedbyRTͲPCR.ThemetabolicactivityofphagocyteswasdeterminedbyNBTͲ
test,phagocytosiswastestedbyflowcytometry,andarginaseactivitywasestimatedby
colorimetric determination of urea. Combined therapy and monotherapy with NSCͲ
631570 resulted in significant inhibition of tumor growth in melanomaͲbearing mice.
Monotherapy with Ukrain was more effective in mice with highͲmetastasizing tumors.
The therapeutic efficacy of NSCͲ631570 used in combination with PAM was more
expressed in mice with lowͲmetastasizing melanoma. Authors concluded the
effectivenessofmonotherapyandcombinedtherapywithNSCͲ631570inthetreatment
of melanoma B16 depends on the biological properties of the tumor and the immune
stateoftheanimal(263).

TheEffectonCysteinProteases

In mice with implanted LSͲlymphosarcoma and HAͲ1 hepatoma, the concentrations of
cystatin C, cathepsin B and cathepsin L were estimated after the treatment with
cyclophosphamideandNSC631570.AnincreasedconcentrationofcystatinCwasfoundonly
40
in hepatomas treatedwith NSC 631570. The concentrations of cathepsin B and cathepsin L
wereincreasedinLSlymphosarcoma.Theseresultsindicateapoptosisasthemechanismof
actionofNSC631570inthesetumormodels(169).

OnthesametumormodelstheeffectofNSC631570oncathepsinDwasstudied.CathepsinD
isanimportantlysosomalprotease,modulatingapoptosisinducedbyinterferonͲgammaand
TNFͲalpha. NSC 631570 combined with cyclophosphamide increased cathepsin D activity in
micewithLSͲlymphosarcoma.NSC631570alonedidnotexertthiseffect(170).

Cystatin C is a well known extracellular protease inhibitor and has been used as a possible
marker of the tumor growth and efficacy of the anticancer therapy (204). The using NSC
631570inmicebroughtabouta4foldincreaseofcystatinCinthetumortissue(171).

In the tests on male mice CBA/C57BI/6J the serum concentration of cystatin C after the
implantationofLewis’adenocarcinomawasonlyhalfashighasinthecontrolgroup.The
combinedtreatmentwithNSC631570andcyclophosphamidenormalisedthecystatinvalues
(218).

On the experimental mice tumors LSͲlymphosarcoma, hepatoma HAͲ1 and Lewis’
adenocarcinoma, the effect of NSC 631570 on the cystatin A (stefin A) was studied. The
treatmentwithNSC631570causedtheincreaseofstefinAintheliverofanimalswithLewis’
adenocarcinoma,butnotinthetumoritself.Inothertumormodelstheconcentrationof
cystatin A both in the liver and tumor tissue did not change. In LSͲlymphosarcoma and
hepatoma HAͲ1 the serum concentration of cystatin A increased in the course of the
treatmentwithNSC631570(220).

The treatment of the hepatoma HAͲ1 implanted mice with NSC 631570 caused the
decelerationofthetumorgrowthandincreasedthesurvivaloftheanimals.Themacrophages
countincreasedwhereasthenumberoftumorcellsintheasciticfluiddiminished.NSC631570
didnotaffecttheactivityofcathepsinBandcathepsinL(199).

MODULATIONOFTHEIMMUNESYSTEM

Unusual for an anticancer agent NSC 631570 possesses some distinct immune properties
(24, 44). In several immune targetͲeffector systems NSC 631570 significantly amplified the
malignotoxic activity of macrophages (231), lymphocytes and NK cells (47), and stimulates
dendritic cells maturation in vitro (258). While the parameters like BͲlymphocytes count,
immune globulin concentrations, complement and acute phase proteins did not changed
significantly, it can be postulated NSC 631570 modulates the cellular part of the immune
systemwhereasthehumoralpartremainsunaffected.

41
ClinicalImmunology

TheincubationofperipherallymphocytesofhealthyblooddonorswithNSC631570resulted
intheincreaseoflymphocyteswiththeTͲhelperphenotype,decreaseofthelymphocyteswith
TͲsuppressorphenotypeaswellasincreaseofTͲhelper/TͲsuppressorratio(7,18).

NSC631570wasadministeredtonineadvancedstagecancerpatients(4withlivercancer,4
withheadandneckcarcinomas,andonebreastcancer).Inthreecasesthetumorsresponded
partiallyonthetherapy,inonecaseaminimalresponsewasnoted,in3casesthediseasewas
stabil, and in 2 cases the tumors did not respond on the treatment. After the therapy, the
numberofTͲhelpercells(CD4)aswellastheCD4/CD8ratioincreased(13).

In eight oncological patients immune parameters were compared before and after the
treatment with NSC 631570. It was revealed NSC 631570 affected basically the thymus
dependant cells (TͲcells). The number of rosetteͲforming TͲlymphocytes was significantly
higher after the treatment. No significant changes were observed in the humoral immune
parameters(22).

Inninemalelungcancerpatientslymphocytessubpopulationsweredeterminedbeforeand
afterthetherapywithNSC631570.ThetherapyresultedinincreasedtotalTͲcellsandreduced
TͲsuppressor fraction. The helperͲsuppressor ratio normalized. There was no sign of the
activation of NK cells, TͲhelpers as well as BͲcells. The restoration of the cellular immunity
correlatedwiththebetterclinicalcourseofthedisease(25).

TheeffectofNSC631570onthefunctionalactivityofmonocytesfrom20patientswithlung
cancer or peritonitis was studied using nitro blue tetrazolium chloride test (NBTͲtest). The
authors reported on the positive effect of NSC 631570 on the functional activity of the
macrophagesaswellasantioxidantsystemsofmonocytesanderythrocytes(46).

23patientswithvarioustumorsweretreatedwithNSC631570andtheimmuneeparameters
were evaluated before and after the therapy. The authors observed the increase of
lymphocytesandthedecreaseofthebloodsedimentationrate.Followingimmunechanges
were also noted: increase of TͲlymphocytes, TͲhelpers, NKͲcytotoxicity, phagocytic activity,
normalisationoftheTͲhelper/TͲsuppressorratio,andoccuranceoflargegranularlymphocytes
(48,106).

NSC 631570 was effective in the therapy of recurring lung diseases in children from the
Chernobylarea(202).

TheEffectontheDendriticCells

Dendriticcellsareimmunecellsthatactasmessengersbetweentheinnateandadaptive
immunity.Theirmainfunctionistoprocessantigenmaterialandpresentitonthesurface
toothercellsoftheimmunesystem,thusfunctioningasantigenͲpresentingcellsandare
seenasthemostpotentpopulationexecutingthisfunction.
42
Intheexperimentswiththemononuclearsfromtheperiphericbloodofhealthypersons
the effect of NSC 631570 on the phenotypic and functional properties of dendritic cells
was studied. The most prominent induction of the expression of the cell surface
molecules CD86 and HLAͲDR was achieved with NSC 631570 at the lowest and highest
concentration, 0.6 µg/mL and 10 µg/mL, respectively. Lipopolysaccharide as standard
comparativeagentinducedsimilarincreaseofthecellsurfacereceptors.
The proliferation index of the incubated lymphocytes was used as the indicator of the
dendriticcellsactivity.AfteradditionofNSC631570totheincubateddendriticcells,the
lymphocyte proliferation index increased from 22.6% up to 32.30% at 0.6 µg/mL or
29.34% at 10 µg/mL, respectively. These values are similar to the one of 31.82%, i.e.
proliferation index achieved at the incubation of lymphocytes with the
phytohemagglutinin. The authors concluded dendritic cells incubated with NSC 631570
are strong stimulators of the lymphocyte proliferation. They postulate also NSC 631570
cantakeanimportantpartintheimmunetherapyofcancer(268).

ImmunologicalpropertiesofUkrain(NSC631570)
NSC631570modulatesthenaturaldefensesystemagainstdevelopingcancer
Underattack–UkrainͲactivatedlymphocytesstartto
recognizethetumorcells.
Victory–UkrainͲactivatedlymphocytesbegintodestroya
tumorcell.
Kissofdeath–Ukrainactivateslymphocytestokillacancer
cell.

Prof. Dr. Andrejs Liepins Memorial University of Newfoundland Faculty of Medicine, St. John’s,
Newfoundland,CANADAA1B3V6

43
TheStudiesinvitroandinvivo

In the tests on alloimmunised mice NSC 631570 augmented the lytic activity of splenic
lymphocytesbyupto48fold.ThelyticactivityoftheILͲ2treatedspleencellsandperitoneal
exudatelymphocyteswerealsoincreasedsignificantlybytheadditionofNSC631570tothe
assaymedium(17,66).

Humanlymphocytesaswellasguineapiglymphocyteswereactivatedmorepronounced
whenincubatedwithUkrainthanwithPHA.InratsNSC631570causedaclearincreaseof
macrophages with NKͲactivity. A similar modulating effect on the macrophages was
observedalsoclinically(49).

It was revealed in the tests on CBA mice and Wistar rats that NSC 631570 stimulates
macrophages. As marker of this activity the enzyme chitotriosidase Ͳ a part of the native
immunitywasused(168).

In a study on intact and thymusͲectomised mice NSC 631570 augmented the endocrine
functionofthymus.AfterNSC631570administration,increasedproductionofsubstanceswith
thymosinͲlikeactivitywasdetected.RepeatedadministrationofNSC631570causeda2fold
riseofTͲcellsinblood,a4.5foldriseoflargegranulocytesandincreaseoftheNKͲactivityof
splenocytes.Theproductionofinterferonandantibodiesaftertheantigenadministrationwas
increasedaswell(180).

The effect of wellͲknown immune modulators interferonͲgamma, NSC 631570 and
pokeweedmitogenontheselectiveuptakeoftechnetiumͲ99m(99mTc)Ͳlabelledtumornecrosis
factor (TNF) was studied in the intramuscular implanted murine embryonic carcinoma. The
highest absolute tumor uptake of 99mTcͲ TNF was achieved when NSC 631570 was used,
followedbyIFNͲɶandpokeweedmitogen(104).

In the experiments on BALB/c and F1 (BALB/c x C57BL/6J) mice it was revealed that NSC
631570 inhibits the allergic sensitization of animals against ovalbumin, expressed in the
weakened IgEͲreaction and decreased histamine release. The incubation of ovalbumin with
NSC631570induceddecreasedantigenicityofthisprotein(84).

The immune modulating effect of NSC 631570 was studied in several studies in mice.
RepeatedsubcutaneousinjectionsofNSC631570tomiceinfectedwiththetwofoldLD50ofE.
coli,S.aureus,orinfluenzavirusincreasedthesurvivalrateoftheanimalssignificantly(60,87,
89).

Whenhumanlymphocyteswereincubatedwithphytohemagglutinin(PHA)andNSC631570,
increased absorption of 3HͲthymidin in the cells was observed. The authors point out the
strongsynergeticeffectofNSC631570andphytohemagglutinin(76).

BymeansofthecellproliferationassaythemitogeniceffectsofPHAandNSC631570on
humanperipheralbloodmononuclearcells(PBMC)werestudied.Itwasrevealedevenashort
pretreatment of the PBMC with NSC 631570 has a strong synergetic effect on the PHAͲ
44
mitogenesis.Consequently,thecellstimulationparametersweremuchhigheraftercombined
stimulationthanafterusingPHAalone(65).

Inexperimentswithmurine(CC57Black/6)macrophagesandrabbitGͲactin,theeffectsofNSC
631570andsanguinarineonphagosomeͲlysosomemembranefusionandactincytoskeleton
were studied. The most stimulating effect on the phagosomeͲlysosome fusion exerted
sanguinarineat10µmolandNSC631570at5µmol.AtthesamedoseNSC631570doubled
thecontentoffibrillaryactininmurineperitonealmacrophages.Moreover,NSC631570and
sanguinarine induced the polymerisation of rabbit globular actin. These effects were doseͲ
dependent. The authors suggest sanguinarine and NSC 631570 can alter intracellular
membranetransport(231).

RADIOPROTECTIVEEFFECT

WhenNSC631570hasbeenusedinclinic,itwasobservedthatthepatientstreatedwiththis
drug tolerate the radiotherapy much better. This gave reason to study radioprotective
propertiesofNSC631570.

In the tests on mice was proven the radioprotective effect of NSC 631570 is much more
pronouncedthanthatofitssourcematerials(132).

Further studies showed NSC 631570 to modulate the cell components of the hemopoietic
system (stem cells, proliferating, maturing, and competent cells) so that the total
radioresistanceincreases(77,133,249).

TheradioprotectiveeffectofNSC631570hasbeenconfirmedbytheinfectionmodelsinmice
whereitseffectwassuperiortotheeffectoftheknownradioprotectorcysteamine(134).

Compared to other drugs NSC 631570 exerted a strong radioprotective effect similar to
lymphokinin(135).

TheseradioprotectivepropertiesofNSC631570wereconfirmedinfurtherstudiesinrats
(172).

NSC631570exertedaprotectiveeffectonthehormonalsystemofirradiatedrats(173).

TheprotectiveeffectofNSC631570againstradiationwasalsostudiedandconfirmedonin
vitromodels.
The effect of NSC 631570 as protector against radiation was studied on human skin
firbroblasts HSF1 and HSF2 as well as lung fibroblasts CCD32ͲLU. As evaluation parameters
werechosencytotoxicity,apoptosisinduction,cellcyclecourse,andtheexpressionofTP53
andp21.Additionally,followingmalignantcelllineswereused:MDAͲMBͲ231(humanbreast
tumor), PAͲTUͲ8902 (pancreas cancer), CCLͲ221 (colorectal cancer), and UͲ138MG
(glioblastoma). The cytotoxicity of NSC 631570 was timeͲ and dose dependent. The
combinationofNSC631570plusionizingradiation(IR)enhancedtoxicityinCCLͲ221andUͲ
45
138MGcells,butnotinMDAͲMBͲ231andPAͲTUͲ8902cells.Moststrikingly,aradioprotective
effect was found in normal human skin and lung fibroblasts. Flow cytometry analyses
supported differentiatial and cell lineͲspecific cytotoxicity of NSC 631570. CCLͲ221 and UͲ
138MGcellsaccumulatedinG2after24htreatmentwithNSC631570,whereasnoalterations
weredetectedintheothertumorcellsandnormalfibroblaststested.Differentialeffectsof
NSC631570inmodulatingradiationtoxicityofhumancancercelllinesanditsprotectiveeffect
in normal human fibroblasts suggest that this agent may be beneficial for clinical
radiochemotherapy(184).

In their next study on the role of the proteins fibronectin and laminin in the radiation
protectionmechanismsofthecells,theresearchersfromtheUniversityofTübingenusedNSC
631570asareferencesubstance(198).

IntheexperimentsonmaleWistarratsirradiatedwithmicrowaves53.57MHzduring14days,
NSC631570wasrevealedtonormalisetheactivityofaminotransferasesALTandASTaswell
astheserumconcentrationofthealphaͲfetoproteincomparedtotheirradiatedcontrolgroup
(233).

Microwavesareelectromagneticwaveswithwavelengthsrangingfromaslongasonemeter
toasshortasonemillimetre,equivalenttofrequenciesbetween300MHzand300GHz.As
the devices operating in this wavelength range have been more and more used, including
therapeutic applications, the importance of the studies of their health effects increases
constantly. The effect of NSC 631570 (7 mg/kg intraperitoneal for 10 days) on the serum
chemistry parameters of male Wistar rats during concomitant microwave irradiation (53.57
GHz,10mW/cm2,20mindailyfor10days)wasstudied.Attheendofthestudynosignificant
changeswereobservedinthecombinedtreatedgroupcomparedtothecontrolgroup.The
authorsconcludedNSC631570canbeusedcombinedwithmicrowavetherapies(242).

TOXICOLOGICSTUDIES

OnaninducedhepatitismodeltheresearchersstudiedwhetherNSC631570canprotectliver
cells from the toxic effect of acetaminophen overdosage. Indeed, NSC 631570 exerted a
protectiveeffectwiththestimulationoflivermacrophages(217).

In the tests on rats, the effects of chelidonine (50 or 100 mg/kg intraperitoneal) and NSC
631570(7or14mg/kgintraperitoneal)onsomebloodchemistryparametersafterintoxication
withcopperchlorideorleadchloridewerestudied.Bothagentsnormalisedtheserumvalues
ofbetaͲ2Ͳmicroglobulin,creatinine,andurea.Theeffectofchelidoninewasmorepronounced
(229,234,236).ThetreatmentwithNSC631570normalisedalsoincreasedvaluesofALTand
alphaͲfetoprotein(193,241).

In male Wistar rats with experimental acute ethylene glycol intoxication (3 or 3.5 g/kg
intraperitoneal), the effect of NSC 631570 (7, 14 or 28 mg/kg intraperitoneal) on blood
chemistryparameterswasstudied.Comparedtothecontrolgroup,the10dayadministration
of NSC 631570 caused a significant decrease of serum urea concentration and increase of
46
serumbetaͲ2Ͳmicroglobulinconcentration(235,257).Inthestudywithlowerethyleneglycol
dose (2.5 g/kg), an increased serum concentration of betaͲ2Ͳmicroglobulin was observed
(240).

In male Wistar rats with experimental acute alcohol intoxication (methanol 4.5 g/kg
intraperitoneal,ethanol3g/kgintraperitoneal,orethyleneglycol3.5g/kgintraperitoneal)the
effectofNSC631570(28mg/kgintraperitonealassingledoseor10dayadministration)onthe
aminotransferaseactivity(ALTandAST)andtheserumalphaͲfetoproteinconcentrationwas
studied.Comparedtothecontrolgroup,thesingleadministrationofNSC631570causedthe
dropoftheincreasedAFPconcentration(excepttheethyleneglycolgroup).TheserumAFP
concentration increased after the 10 day administration of NSC 631570. There were no
changesinotherparameterscomparedtothecontrol(237,248,256,257).

To study the effect of NSC 631570 on some chemistry parameters in the acute methanol
intoxication,WistarratsweretreatedwithNSC631570for10days.Thetherapyalleviatedthe
unfavourableconsequencesofthemethanolintoxication,expressedbythenormalizationof
theincreasedserumconcentrationsofbetaͲ2Ͳmicroglobulinandurea(192,196,227,228).

NORMALISATIONOFTHEMETABOLISM

BoneMetabolismandOsteoporosis

A series ofanimal testswas aimed to studytheeffect of NSC 631570 on bone density and
mineralmetabolism.

Ina6monthstudyonfemaleovariectomizedrats,NSC631570hasbeenrevealedtoinhibit
the development of some indications of early osteoporosis (78). The blood parametersand
transaminaseactivityintheNSC631570groupdidnotdifferfromonesinthecontrolgroup
(79). Prolactin and progesteroneconcentrationswereelevated,those of corticosterone and
aldosteronediminishedcomparedtothecontrolovariectomizedgroup(57,80).

ThetreatmentofmaturefemaleratswithNSC631570athighdosagehadnonegativeeffect
onthebonemineraldensity.Aslightdecreaseofbonemineralcontentwasobserved(128).

Afterintermittent3monthadministrationofNSC631570athighdosagetoovariectomized
femaleratsthebonemineraldensitydecreased(129).

The effect of NSC 631570 on the bone metabolism in rats was reviewed in an article. The
authorconcludedthisdrugtoaffectespeciallytheestrogendependantmechanismsandhas
protectiveeffectagainstosteoporosis(174).

Inasetofanimaltests,ratfemurwasusedasamodelforthestudyofthelongͲtermeffectof
NSC631570onvariousboneparameters.NSC631570wasrevealednottodiminishthebone
strengthanddensityalsoathigherdosage(175,176).
47
It was also studied how various doses of NSC 631570 affect the intensity of electron spin
resonance(ESR)signalinintactandovariectomizedrats.Theintensityofthesignalcorrelates
directlywiththeamountoffreeradicalsinthetissue.Thesignalintensitywasthelowestinthe
ovariectomizedgroupwithhighestNSC631570doseandthehighestintheintactgroupatthe
lowestdoseofNSC631570(177).

In intact female rats the effect of NSC 631570 on the hormones involved into calcium
metabolism was studied. In the highest dosage group the serum concentrations of
corticosteroneandprogesteronedecreasedsignificantlyandnonͲsignificantly,respectively.In
the lowest dosage group the serum concentration of parathormone increased significantly.
Theserumvaluesofcalcitoninwerenotaffectedineithergroup(223).

TheeffectofNSC631570onthesamehormoneswasalsostudiedinfemaleovariectomized
rats.Inthemiddledosegroupthecorticosteroneserumconcentrationdropped.Therewere
nootherchangesinhormonevaluesinalldosegroups(224).

InthetestsinmaleWistarratsirradiatedwith53.57MHzmicrowavesfor14days,NSC631570
exertedpracticallynoeffectonthewatercontentaswellasorganicandinorganicphasesof
pelvisbonecomparedtotheirradiatedcontrolgroup(232).

TheeffectsofNSC631570atdifferentdosesand/orstrontiumontherattoothintertubular
dentine were analysed in cuts perpendicular to the dentinal tubes. The tooth surfaces and
crossͲsectionmorphologyandroughnesswereinvestigatedwithatomicforcemicroscopy.The
crossͲsection surface of intertubular dentine was analysed by roughness and fractal
parameters.Histogramswerepreparedforthetypicalsamplesfromallgroupsteethanalysed.
Dentinecrosssectionsurfacesshowedsignificantdifferencesbetweenthenanostructuresof
normalratteethandthosefromanimaltreatedwithNSC631570andstrontium(260).

THEEFFECTONVARIOUSENZYMES

In the tests on liver cells NSC 631570 was revealed to inhibit the alcohol dehydrogenase
activity(178,253).

TheeffectofNSC631570ontheactivityoftrypsinͲlikeenzymeswasalsostudied(183,222).

TheeffectofNSC631570ontheconcentrationofthevasoactiveintestinalpeptide(VIP)was
studiedonthediabetesmodelinmiceaswellasonintactanimals.NSC631570exertedno
effectontheVIPconcentrationinintactmice.Indiabeticmicethe10dayadministrationof
NSC631570causedasignificantincreaseoftheVIPconcentrationinthelowestdosegroup
(194,225).

In the experiments on the rat liver the researchers revealed that NSC 631570, beside
chelidonine, caused the strongest inhibition of the enzyme monoamine oxidase (MAO),
indicatingitsantidepressantproperties(197,252).
48
InareviewtheresearcherssummarizedthearticlesontheeffectofNSC631570ontheamino
acidmetabolism.TheynotedNSC631570exertsdifferenteffectsontheaminoacidpoolsin
thebodyandinthemalignanttissue(213).

In a set of experiments in rats the effects of NSC 631570 on various liver enzymes were
studied. In a test, the effects of the NSC 631570 seven day administration on the lipid
peroxidationandantioxidativefunctionoftheratliverwereexplored.Atdailydoseof2
mg/kgNSC631570theserumconcentrationofreducedglutathionedecreasedat25%andthe
antioxidativefunctionoftheratliverdecreasedat49%.Theglutathionereductaseactivityin
the postmitochondrial fraction of the rat liver increased at 43% compared to the control
group.Therewasnoactivationofthelipidperoxidationaftertheadministrationof2mg/kg
NSC 631570, and thecatalase as well as peroxidise activity did not differfrom those in the
controlgroup.TheauthorssuggestedanassumptionNSC631570tocauseanoxidativestress
inthetumorresultinginapoptosis(214).

The effects of NSC 631570 on the liver enzymes involved into the drug metabolism were
studied.AfterthesixdayadministrationofNSC631570atadailydoseof2mg/kg,theactivity
of aminopyrineͲNͲdemethylase increased by 35% and the one of glutathioneͲSͲ
transferaseby55%.TheconcentrationsofmicrosomalcytochromesP450andb5aswell
astherateofethylmorphineͲNͲdemethylationwerenotaffected(215).

INTERACTIONWITHOTHERDRUGS

NonͲOpioidAnalgesics

In mice and rats the interaction of NSC631570andaminophenazonewasstudied.Itwas
foundthatNSC631570affectstheanalgesiceffectofaminophenazoneinvariousways.Inthe
writhingsyndrometestinmiceaswellasintailͲflicktestinratstheantinoceptiveeffectofthe
analgesic was potentiated, whereas in the hotͲplate test the analgesic effect of
aminophenazonewasreduced(20).

TheanalgesiceffectofNSC631570wasaugmentedbythenitricoxidesynthaseinhibitorsin
mice.TheseresultssuggesttheendogenousnitricoxidecanmodifytheanalgesiceffectofNSC
631570(130).

OpioidAnalgesics

The tests on mice and rats revealed NSC 631570 to modify the antinoceptive effect of
opiates.Inmice,forexample,NSC631570potentiatedtheanalgesicactionofmorphineinthe
hotplatetestandinthetailflicktest,however,reducedthiseffectinthewrithingsyndrome
test(35).

In the studies in mice was revealed the 10 day intraperitoneal administration of NSC
631570athighdosehasananalgesiceffectinmice.Combinedadministrationofmorphine
49
and NSC 631570 reduced their antinoceptive effects reciprocally. The authors propose to
avoidcombinedclinicaluseofthesedrugs(85,86).

The analgesic action of NSC 631570 in mice was completelyabolished by naltrexon, a pure
opioidantagonistactingonallopioidreceptorsasacompetitiveantagonist(131).

Streptozotocin

Thestreptozotocindiabetesmodelwasusedinratstoexplorehowchangestheliverand
kidney function in these animals under the impact of NSC 631570. The 10 day
administrationofNSC631570tostreptozotocinratsdidnotchangetheserumcreatinine
concentration, but increased the urea value. The authors concluded NSC631570should
notbecombinedwithstreptozotocin(195,226,239).

PorphyrinDerivates

In the tests on murine sarcoma, mammary carcinoma, human colon carcinoma and
melanoma cell lines NSC 631570 and porphyrin amino acid derivates to have synergetic
actionagainstcancercelllines(53,83).

Anticonvulsants

InAlbinomicetheinteractionofNSC631570andvariousanticonvulsantssuchasdiazepam,
carbamazepine, diphenylhydantoin, phenobarbital, and valproate was studied. NSC 631570
potentiatedthe protective effect of valproate, whereas the effects of other anticonvulsants
werenotaffected(34).

INTERACTIONWITHOTHERTHERAPYMODALITIES

Localhyperthermia

Hyperthermiaisatypeoftreatmentinwhichbodytissueisexposedtohightemperatures
(upto45°C),todamageandkillcancercells,ortomakecancercellsmoresensitivetothe
effects of radiation and certain anticancer drugs. Local hyperthermia treatment (heat
applied to a very small area, such as a tumor) is a wellͲestablished cancer treatment
methodwithasimplebasicprinciple:Ifariseintemperatureto45°Ccanbeobtainedfor
one hour within a cancer tumor, the cancer cells will be destroyed. Primary malignant
tumors have a bad blood circulation, which make them more sensitive to changes in
temperature. The therapy with NSC 631570 has been successfully combined with local
hyperthermiasincemanyyears(115,144,208).
50
Inhisspeechatthe5thViennaDialogontheHolisticMedicine,Dr.B.Aschhoffreported
on his experience in the NSC 631570 therapy and local hyperthermia. Summing up,
followingtheseswerenoted:significantimprovementofthequalityoflife;fewadverse
effects;NSC631570issafeandcanbeusedinchildrenalso;wideindicationrangeofthe
therapy(142).

EndovascularLaserTherapy/PhotodynamicTherapy

Theendovascularlasertherapyasapartofphotodynamictherapy(PDT)isanewmethod
for systemic laser treatment and energy transfer to the human body. For therapeutic
application red, infrared, green, and blue lasers are used. The photon stream applied
intravenously leads to an improved microcirculation, activation of the immune system
and mitochondria. Recently, NSC 631570 has been used as a sensitizer (Weber M, ‘The
intravenous laser blood irradiation, a new therapeutic approach in immunology and
cancertherapy”,presentationatthe2ndInternationalConferenceonDrugDiscoveryand
Therapy,SLͲ341,Dubai,UAE,2010).

NSC 631570 was administered to the patients with rheumatic diseases or high
susceptibility to infections. In the lymphocytes from both patients group and from a
controlgroup,expressionofIgG,proliferationmarkerKiͲ67andothermarkermolecules
wereestimated. Therewere no significant changes in the control group whereas in the
NSC 631570 group the expression of IgG and KiͲ67 increased significantly. Further
increaseofmarkerexpressionwasachievedusingadditionalendovascularlowͲlevellaser
therapy. Circulating tumor cells from cancer patients were incubated with NSC 631570.
PatientsweretreatedwithNSC631570aloneorwithNSC631570andendovascularlaser.
Thetumormassreductionwasachievedinbothgroupsbutinthecombinedgroupthis
effect was more pronounced (Andrae F, ‘Ukrain based laser therapy in oncology’,
presentationatthe2ndInternationalConferenceonDrugDiscoveryandTherapy,SLͲ274,
Dubai,UAE,2010).

Ozone

Empiric experience revealed NSC 631570 should not be combined with the ozone
therapy. Generally, NSC 631570 should preferably be used as monotherapy. Other
therapymodalitiescanbeusedinthebreaksbetweenthetreatmentcycles.

Others

Inapilotstudyitwaselaboratedhowamethodfordeterminationofanoptimaldosage
for the therapy with NSC 631570 could be elaborated (the same for interferonͲalpha,
too).ThemethodisbasedontheestimationofSS/SHgroupsratioinserum(138).
51
II.SAFETY

AttherapeuticdoseNSC631570hasnoappreciableadverseeffectsanddoesnotdamage
healthycellsbutonlyattackscancercells.Duetoitsveryhightherapeuticindexof1250–
in contrast to common cytostatics with a low TI of 1.4Ͳ1.8 – there is no danger of an
overdosewithUkraintherapy(therapeuticindexistheratiobetweenthetoxicdoseand
thetherapeuticdoseofadrug,usedasameasureoftherelativesafetyofthedrugfora
particular treatment. From ‘The American Heritage® Dictionary of the English Language,
4th Edition’). Ukrain also does not cause necroses when administered intramuscular,
whichisaproofforitssafety(37).

The Austrian Research Center Seibersdorf is the leading Austrian research institution in
lifesciences.NowitisapartoftheAustrianInstituteofTechnology(AIT),thelargestnonͲ
universityresearchinstitutioninAustria.AttheSeibersdorfbranchofAITthestateͲofͲart
toxicological studies are performed according to the GLP guidelines (Good Laboratory
Practice). Following GLP conformed studies with NSC 631570 were performed at the
ARCS.

AcuteIntravenousToxicitywithRats

The study was performed in conformance with the ECͲGuideline 92/69 and the OECDͲ
Guideline 401. The test substance was administered undiluted as a slow intravenous
injectiontomaleandfemaleHim:OFAratsatdosesof33mg/kg,57mg/kg,or100mg/kg
(onlyfemales)bodyweight(b.w.).Theadministrationinducedimmediateeffects,which,
if not lethal, soon lead to an almost complete recovery. Most probable cause of death
wasashiftinthebloodpHorinthebloodionhomeostasis.Malesweremoresusceptible
than females. Based on the results obtained, the LD50 (intravenous) of the active
substancewascalculatedas43mg/kgb.w.formalesand76mg/kgb.w.forfemales(151,
OEFZSͲAͲ4483,October1998).

AcuteIntravenousToxicitywithMice

ThestudywasperformedaccordingtotheDirective92/69/EECandtheOECDGuideline
401,1987.NSC631570wasadministeredasaslowintravenousinjectiontothreegroups
offivemaleandoffivefemaleHim:OF1,SPFmiceatdosesof33mg/kgb.w.,74mg/kg
b.w., and 165 mg/kg b.w. All animals in the high dose group and two males and three
females in the mid dose group died. All other animals survived until 14 days after
administration.Allsurvivedanimalswerenormalattheendofthestudy.Allanimalswere
normal at necropsy. There was no marked sex difference in the response to the test
substance. Based on the results obtained, the LD50 (intravenous) was calculated as 80
mg/kgb.w.formalesand68mg/kgb.w.forfemales(OEFZSͲLͲ0400,May2000).
52
AcuteIntramuscularToxicitywithRats

The aim of the study was to reveal acute toxic effects of NSC 631570 after a single
intramuscular administration to rats. The study was performed according to the ECͲ
Directive 87/176/EWG and the OECDͲGuideline 401, as far as these were useful for
intramuscular administration. The test substance was administered undiluted as an
intramuscular injection to five male and five female Him:OFA rats at the highest
technicallyfeasibledosefortheintendedroute,i.e.150mgactiveingredientperkgb.w.
Allanimalssurviveduntilthescheduledterminationofthestudy.Bodyweightgainwas
notimpaired.Sedationandlesspronounceddisturbedlocomotionwasnotedontheday
of the administration. Local changes at the injection site (crusts) werepresent in about
half of the animals. There was no sex difference in the response to the test substance.
TheauthorsconcludedintramuscularinjectionofNSC631570inthehighestfeasibledose
induced some transient signs of minor clinical importance but was otherwise well
toleratedanddidnotbecomelifethreatening.Basedontheresultsobtainedinthisstudy
theLD50(intramuscular)ofNSC631570wascalculatedtobehigherthan150mg/kgb.w.
(151,OEFZSͲLͲ0194,October1999).

AcuteOralToxicityStudywithRats

This study aimed to investigate acute toxic effects of NSC 631570 after a single oral
administration to rats and was performed according to the ECͲDirective 92/69 and the
OECD Guideline 401. NSC 631570 concentrated was administered undiluted once by
stomachintubationtothreegroupsoffivefemaleHim:OFASpragueDawleyratsandto
onegroupoffivemaleSpragueDawleyratsatthedosesof450mg/kgb.w.,810mg/kg
b.w.,and1500mg/kgb.w.(females)or810mg/kgb.w.(males).Allfemalesinthehighest
dose group died spontaneously on the day of administration. All females in both other
dosagegroupsaswellasallmalessurviveduntilthescheduledtermination.Allanimalsof
themidandhighdosedgroupswereaffectedwithmostofthesignsobservedontheday
ofadministrationofthetestsubstance.Theeffectslasteduntilmaximalthreedaysafter
administration.Allsurvivinganimalswerenormalattheendofthestudy.Therewasno
relevantsexdifferenceintheresponsetothetestsubstance.
Hence the test substance induced immediately effects which, if not lethal, led to an
almostcompleterecoverysoon.TheLD50(oral,females)wascalculatedas1110mg/kg
b.w.(151,OEFZSͲLͲ0195,October1999).

LocalTolerabilityStudy

NSC 631570 was administered as a slow intravenous, intraarterial, paravenous or
intramuscular injection to two male and two female rabbits per route to study its local
tolerability.Normalsalinewasadministeredcorrespondinglytotheotherearormuscle
of each animal as a control. NSC 631570 was well tolerated at intravenous and
intraarterialadministration.Theparavenousinjectioncausedmildlocalirritation,andthe
intramuscular administration caused a mild to moderate local inflammation. There was
nosexdifferenceintheresponsetothetestsubstance(OEFZSͲAͲ4204,October1997).
53

MicronucleusTestwithMice

The study was performed to detect the possible production of micronuclei induced by
NSC631570asaresultofchromosomaldamageorofdamagetothemitoticapparatusin
aninvivotestsystem.NSC631570wasdilutedwithnormalsalineandadministeredonce
atdosesof1.25,2.50,or5.00ml/kgb.w.intravenouslytothreegroupsoffivemaleand
five female Crl:NMRI BR mice each. Additionally, one high dose group of one male and
onefemalespareanimalwasincludedtoreplacepossibleunscheduleddeathsinthehigh
dosegroup.Twonegativecontrolgroups(normalsaline)andonepositivecontrolgroup
(thiotepa) were also included into the study. Preparation of bone marrow cells and
investigationswereperformedinconformancewiththeOECDGuideline474.
All animals survived until scheduled sacrifices. Thiotepa (positive control group) caused
cytotoxicityandproducedmicronucleiinpolychromaticerythrocytes.NSC631570didnot
cause cytotoxicity. All data were in the range of historical negative control data. There
were no significant differences in micronucleated normochromatic erythrocytes (MNE)
betweenthetestsubstancegroupanimalsofbothsexesandthecorrespondingnegative
controls, neither 24 nor 38 hours after administration. Also no statistically significant
differences in the amounts of micronucleated polychromatic erythrocytes (MPE) were
notedinanysexatanydoseused.TheratesofMPEwereatbothsamplingtimeswithin
thelimitsofhistoricalnegativecontrolgroups.Nosexdifferenceintheresponsetothe
testsubstancewasnoted.TheauthorsconcludedNSC631570nottocausecytotoxicityto
the bone marrow at doses up to 5 mg/kg b.w. and not to produce micronuclei in the
polychromatic erythrocytes in mice of both sexes at the doses used (OEFZSͲLͲ0225,
November1999).
Similar results were obtained in the second micronucleus study with NSC 631570
concentrated(OEFZSͲLͲ0224,November1999).

SalmonellatyphimuriumReverseMutationTest

NSC631570wastestedformutagenicactivityintheS.typhimuriumreversemutationtest
(Amestest)accordingtotheOECDGuideline471andtheEECGuideline92/69,partB14.
Thetestsubstancewastestedattherangeofconcentrationsaccordingtothedirectplate
incorporation method without and with external metabolisation system S9Ͳmix. The
bacterial strains S. typhimurium TA97a, TA98, TA100, and TA1535 were used as test
system. Negative and positive controls were included and an independent repetition of
theexperimentwasperformed.ThetestsubstancewasnottoxictotheS.typhimurium
strains used. According to the results obtained in this study, NSC 631570 is nonͲ
mutagenic in the Ames test with the strains TA97a, TA98, TA100, TA102, and TA1535
(OEFZSͲLͲ0003,January1999).

LiverToxicity

As the source materials for the production of NSC 631570 Ͳ celandine alkaloids and
thiotepa are toxic for liver cells, a study was initiated to evaluate the possible toxic
54
potential of NSC 631570 to the liver. The study was performed in rats and proved NSC
631570isnottoxictotheratliver(Müller2004,originalreport).

OtherToxicityStudies

ManyothertoxicitystudieswereperformedinEasternEurope(15,16,105,123,127).
The first toxicity studies were performed on Albino Swiss mice and Wistar rats. NSC
631570wasadministeredintraperitoneallyatthesingledailydoseof0.025,0.05,and0.1
of LD50 (e.g. 4.75, 9.5, 19 mg/kg in mice and 7, 14 and 28 mg/kg in rats) during three
months.Thetreatmenthadnoeffectontheorganweightwithexceptofspleeninrats
where the organ weight was up to 3fold higher than in the control group (29). The
estimation of catecholamines in brain revealed the three month administration of NSC
631570 at middle and higher dose diminished the dopamine concentration in mice and
rats.Theconcentrationsofnoradrenalin,5Ͳhydroxytryptamineand5Ͳhydroxyindolacetat
were not changed (29). The single administration of NSC 631570 had no effect on the
serum prolactin concentration in rats. On the contrary, after the three month
administration of NSC 631570 the serum prolactin concentration increased in all dose
groupscomparedtothecontrol(32).

Regarding blood count, the administration of NSC 631570 had similar effects in the
middle and higher dose groups: increase of white blood cells (WBC) and decrease of
platelets. The changes in the differential count were also observed, e.g. lymphocytes
increase and neutrophil bands decrease. No significant changes in red blood cells (RBC)
wereobservedcomparedtothecontrol(33).

Alsotherewerenochangesinthetransaminaseactivityinrats.Inmice,increaseofALT
andASTactivityoccurredinthemiddleandhigherdosegroups.Aslightdecreaseofthe
totalproteinwasobservedinmalemiceinthegroups9.5and19.5mg/kg,infemalemice
onlyinthegroup19mg/kg.ThesingleadministrationofNSC631570didnotaffectthe
evaluatedparameters(31).

IntheexperimentswithhamstercellsitwasrevealedNSC631570isnotmutagenaswell
asnotgenotoxicanddoesnotcausemorphologiccelltransformations(19).

Tests in mice and guinea pigs have revealed NSC 631570 not to cause anaphylactic
sensitization(23).

Inthetestsinrats,NSC631570wasconfirmednottoexertembryotoxicorteratogenic
effect. In hamsters, theembryotoxic effect was observed at the very high dosage of 28
mg/kgbodyweight(30).

In a series of experiments the effect of the six week administration of NSC 631570 in
rabbitswasstudied(subacutetoxicity).
Thedailytreatmentatthreevariousdosagecausednoeffectontheorganmorphologyand
bodymassoftheanimals.Inbloodcount,thenumbersofredbloodcellsandwhitebloodcells
didnotchange.Inthehighdosagegroup,thepercentagesoflymphocytes,monocytes,and
55
eosinophilsincreased.Thebloodchemistryparameterswerenotaffectedapartfromincrease
ofureaanduricacid(124).

Amongsexhormones,estradiolincreasedinsomegroupsasdidtestosteroneinthelowest
dosemalegroup.Infemales,progesteroneincreasedonlyinthehighestdosegroup(125).

NSC631570causedtheincreaseofthyroidhormonesinmales.Infemales,triiodothyronine
increasedandthyroxinconcentrationdidnotchange(126).

InastudyinmaleWistarratstheresearchersrevealedthatthesixdayadministrationof
NSC631570inbothdosesof1mg/kgand2mg/kgcausednosignificantchangesinthe
following parameters: albumin, mucopolysaccharides, aminotransferase activity, and
thymol test. Similarly unaffected compared to the control group was the liver tissue
morphology. Significantly lower was the blood concentration of the middle molecules
(216).

IntheWistarratswithimplantedGuerincarcinoma,NSC631570wasrevealedtoreduce
thenumberofthiolgroupsinthetumorhomogenates(121).

PHARMACOKINETICS

Pilotstudiesofpharmacokineticsgavefirstsuggestionsonthemethodswhichshouldbe
usedinthelaterstudies(105,127).

ToestimatetheplasmaconcentrationandpharmacokineticparametersofNSC631570at
intravenousadministration,firstamethodforitsdeterminationinplasmawasdeveloped
(152).ThisenabledconsequentlythestudyofpharmacokineticsofNSC631570inrats.It
wasrevealedthetumortissueandtheliverhadthestrongestaffinitytoNSC631570.In
brainandmusclestheNSC631570accumulationwastheleast(153).

BIOPHYSICALPROPERTIES

The examinations with physical methods (spectrometry, polarized light microscopy)
revealed NSC 631570 to be resistant against the UV light of middle intensity. The
absorptionpeaks210and230nmcanbeusedforthedetectionofNSC631570inplasma
(50,81).

In the tests with the rat liver homogenates the oxygen consumption was detected by
meansofpolarography.TheadditionofNSC631570causedcomplexredoxreactionsin
thesubstrate.ThiswasdependantontheNADPinducedoxidation(82).
56
III.QUALITY

The proof of quality has been described in the Pharmacopoea Austriaca VIII, European
PharmacopoeiaandintheDeutschesArzneibuch(GermanPharmacopoeia),6thedition.

GreatercelandineͲExtractfromtheEuropeanPharmacopoeia6.0
6.0/1861
GREATERCELANDINE
Chelidoniiherba
DEFINITION
Dried,wholeorcutaerialpartsofChelidoniummajusL.collectedduringflowering.
Content:minimum0.6percentoftotalalkaloids,expressedaschelidonine(C20H19NO5;Mr353.4)
(drieddrug).
CHARACTERS
MacroscopicandmicroscopiccharactersdescribedunderidentificationtestsAandB.
IDENTIFICATION
A.Thestemsarerounded,ribbed,yellowishtogreenishͲbrown,somewhatpubescent,about3mmto
7mm in diameter, hollow and mostly collapsed. The leaves are thin, irregularly pinnate, the
leafletsovatetooblongwithcoarselydentatemargins,theterminalleafletoftenthreeͲlobed;the
adaxial surface is bluishͲgreen and glabrous, the abaxial surface paler and pubescent, especially
on the veins. The flowers have 2deeply concavoͲconvex sepals, readily removed, and 4yellow,
broadlyovate,spreadingpetalsabout8mmto10mmlong;thestamensarenumerous,yellow,
andashortstylearisesfromasuperiorovary;long,capsular,immaturefruitsarerarelypresent.
B.Reducetoapowder(355).ThepowderisdarkgreyishͲgreentobrownishͲgreen.Examineundera
microscope using chloral hydrate solutionR. The powder shows the following diagnostic
characters:numerousfragmentsofleavesinsurfaceview,theepidermalcellswithsinuouswalls;
anomocyticstomata(2.8.3)occurontheabaxialsurfaceonly;coveringtrichomeslong,uniseriate,
withthinwallsandusuallyfragmented;vasculartissuefromtheleavesandstemswithgroupsof
fibres, pitted and spirally thickened vessels and associated latex tubes with yellowishͲbrown
contents; occasional fragments of the corolla with thinͲwalled, partly papillose cells containing
numerouspaleyellowdropletsofoil;sphericalpollengrainsabout30µmto40µmindiameter
with3poresandafinelypittedexine.
C.ThinͲlayerchromatography(2.2.27).
Test solution. To 0.4g of the powdered drug (710) add 50ml of dilute acetic acidR. Boil the
mixtureunderarefluxcondenserinawaterͲbathfor30min.Coolandfilter.Tothefiltrateadd
concentrated ammoniaR until a strong alkaline reaction is produced. Shake with 30ml of
methylene chlorideR. Dry the organic layer over anhydrous sodium sulphateR, filter and
evaporateinvacuotodryness.Dissolvetheresiduein1.0mlofmethanolR.
Referencesolution.Dissolve2mgofpapaverinehydrochlorideRand2mgofmethylredRin10ml
ofalcoholR.
Plate:TLCsilicagelplateR.
Mobilephase:anhydrousformicacidR,waterR,propanolR(1:9:90V/V/V).
Application:10µlasbands.
Development:overapathof10cm.
Drying:inair.
Detection: spray with potassium iodobismuthate solutionR and dry the plate in air; spray with
sodiumnitritesolutionRandallowtheplatetodryinair;examineindaylight.
Results: see below the sequence of the zones present in the chromatograms obtained with the
referencesolutionandthetestsolution.Furthermore,otherweakerzonesmaybepresentinthe
chromatogramobtainedwiththetestsolution.
57
Topoftheplate
_______ _______
Methylred:aredzone Abrownzone
Abrownzone
Papaverine:agreyishͲbrownzone AgreyishͲbrownzone
_______ _______

Abrownzone
Abrownzone
Referencesolution Testsolution
TESTS
Foreignmatter(2.8.2):maximum10percent.
Loss on drying (2.2.32): maximum 10.0per cent, determined on 1.000g of the powdered drug
(355)bydryinginanovenat100Ͳ105°Cfor2h.
Totalash(2.4.16):maximum13.0percent.
ASSAY
Testsolution.To0.750gofthepowdereddrug(710),add200mlofdiluteaceticacidRandheat
on a waterͲbath for 30min, shaking frequently. Cool and dilute to 250.0ml with dilute acetic
acidR. Filter. Discard the first 20ml of the filtrate. To 30.0ml of the filtrate add 6.0ml of
concentrated ammoniaR and 100.0ml of methylene chlorideR. Shake for 30min. Separate the
organiclayer,place50.0mlina100mlroundͲbottomedflaskandevaporatetodrynessinvacuo
atatemperaturenotexceeding40°C.Dissolvetheresidueinabout2Ͳ3mlofalcoholR,warming
slightly.Transferthesolutiontoa25mlvolumetricflaskbyrinsingtheroundͲbottomedflaskwith
dilutesulphuricacidRanddiluteto25.0mlwiththesamesolvent.To5.0mlofthesolution,add
5.0ml of a 10g/l solution of chromotropic acid, sodium saltR in sulphuric acidR in a 25ml
volumetric flask, stopper the flask and mix carefully. Dilute to 25.0ml with sulphuric acidR and
stoppertheflask.
Compensation solution. At the same time and in the same manner, place in a 25ml volumetric
flask5.0mlofdilutesulphuricacidRand5.0mlofa10g/lsolutionofchromotropicacid,sodium
saltR in sulphuric acidR, stopper the flask and mix carefully. Dilute to 25.0ml with sulphuric
acidRandstoppertheflask.
Place both solutions on a waterͲbath for 10min. Cool to about 20°C and dilute if necessary to
25.0mlwithsulphuricacidR.Measuretheabsorbance(2.2.25)ofthetestsolutionat570nm.
Calculate the percentage content of total alkaloids, expressed as chelidonine, from the
expression:

Ax2.23
m

i.e.takingthespecificabsorbanceofchelidoninetobe933.
A = absorbanceat570nm,
m = massofthesubstancetobeexamined,ingrams.

58
Thiotepa–ExtractfromtheUSPharmacopoeia,24thedition

„Thiotepa

C6H12N3PS189.22
Aziridine,1,1',1"ͲphosphinothioylidynetrisͲ,
Tris(1Ͳaziridinyl)phosphinesulfide[52Ͳ24Ͳ4]

» Thiotepa contains not less than 97.0 percent and not more than 102.0 percent of
C6H12N3PS,calculatedontheanhydrousbasis.
Caution — Great care should be taken to prevent inhaling particles of Thiotepa or
exposingtheskintoit.

Packaging and storage — Preserve in tight, lightͲresistant containers, and store in a
refrigerator.
USPReferenceStandards(11)—USPThiotepaRS.
Identification,InfraredAbsorption(197S)—Solution:3in400.Medium:carbondisulfide.
Meltingrange(741):between52°and37°
Water,MethodI(92I):notmorethan2.0%.
Assay—
Mobile phase — Prepare a suitable filtered and degassed mixture of water and
acetonitrile (9:1). Make adjustments if necessary (see System Suitability under
Chromatography(621)).
Standard preparation— Dissolve an accurately weighed quantity of USP Thiotepa RS in
Mobilephasetoobtainasolutionhavingaknownconcentrationofabout1.5mgpermL.
Assaypreparation—Transferabout75mgofThiotepa,accuratelyweighed,toa50ͲmL
volumetricflask,dissolveinMobilephase,dilutewithMobilephasetovolume,andmix.
Resolutionsolution—Transferabout10mgofUSPThiotepaRStoa4ͲmLvial,add2mL
ofmethanol,andmix.Add50µLof0.1%phosphoricacidsolution.Placeacaponthevial,
andheatat65°for50seconds.Coolthesolution,add1mLofmethanol,andmix.
Chromatographic system (see Chromatography (621) — The liquid chromatograph is
equippedwitha215Ͳnmdetectoranda4Ͳmmx15ͲcmcolumnthatcontainspackingL1.
The flow rate is about 0.8 mL per minute. Chromatograph the Resolution solution, and
recordthepeakresponsesasdirectedunderProcedure:therelativeretentiontimesare
about1.25formethoxythiotepaand1.0forthiotepa,andtheresolution,R,betweenthe
methoxythiotepa peak and the thiotepa peak is not less than 3.0. Chromatograph the
Standardpreparation,andrecordtheresponsesasdirectedunderProcedure:thetailing
factorforthethiotepapeakisnotmorethan1.8,thecolumnefficiencyisnotlessthan
2600theoreticalplates,andtherelativestandarddeviationforreplicateinjectionsisnot
morethan2.0%.
Procedure—Separatelyinjectequalvolumes(about10µL)oftheStandardpreparation
and the Assay preparation into the chromatograph, record the chromatograms, and
measuretheresponsesforthemajorpeaks.Calculatethequantity,inmg,ofC6H12N3PSin
theportionofThiotepatakenbytheformula:

50C(ru/rs),
59
in which C is the concentration, in mg per mL, of USP Thiotepa RS in the Standard
preparation, and ru and rs are the thiotepa peak responses obtained from the Assay
preparationandtheStandardpreparation,respectively.”

DuringtheproductionofUkrainthiotepaiswashedoutsothatthereisnothiotepainthe
end product. This has been proved using the most sensitive method of gas
chromatography.

Stability

The stability of the Ukrain solution for injectionwas investigated in a real time stability
studywith3batchesstoredfor60monthsat25°Cand60%relativehumidityaswellas
for 6 months at 40°C and 75% relative humidity (accelerated condition stability study).
ThestudywasperformedaccordingtotheOECDGLPGuidelines.Attheendofthestudy
allparameterswerewithinreferencerangehavingprovedthestabilityoftheendproduct
(Stability Study of Ukrain Ampoules Stored under Controlled Conditions. Final Study
Report.March2003.SGSLabSimonS.A.HealthcareandBioscienceServices796.529).

60
BIBLIOGRAPHY

(1) Nowicky JW. New ImmunoͲstimulating antiͲcancer preparation "Ukrain". 13th
InternationalCongressofChemotherapy,Vienna,28thAugustto2ndSeptember,
57,1983,PS12533/AͲ6,part288/
(2) NowickyJW.CancerTreatmentUsingAnticancerPreparationAlkaloidDerivative
Ukrain. IV Mediterranean Congress of Chemotherapy, 19Ͳ25 October 1984,
Rhodes,Greece,Chemioterapia,Supplementton.2,Volume4,1169,April1985.
(3) NowickyJ,GreifM,HamlerF,HiesmayrW,StaubW.BiologicalActivityofUkrain
inVitroandinVivo.VMediterraneanCongressofChemotherapy.26OctoberͲ1
November1986Cairo,Egypt,Chemioterapia,Supplementton.2,Volume6,683,
June1987.
(4) NowickyJW,GreifM,HamlerF,HiesmayrW,StaubW.MacroscopicUVͲMarking
throughAffinity.JournalofTumorMarkerOncology,Volume3,Number4,463,
1988.
(5) Nowicky J, Hiesmayr W, Nowicky W. Sensitisation for Specific Lysis in TargetͲ
EffectorͲSystem with Derivatives of Chelidonium majus Alkaloids Ͳ Ukrain.
Extracted from the Proceedings of the 16th International Congress of
Chemotherapy;852.1,June1989,Israel.
(6) Nowicky JW. Biological and physiological effects of Ukrain. Journal of Cancer
ResearchandClinicalOncology,SupplementVol.116,A3.112.46,1990.
(7) Slesak B, Nowicky JW, Harlozinska A. In vitro effect of thiophosphoric acid
derivatives from Chelidonium majus L. on normal lymphocyte subpopulations.
JournalofCancerResearchandClinicalOncology,SupplementVol.116,A3.112.
50,1990.
(8) Liepins A. Enhancement of cell mediated lysis of tumor cells by Chelidonium
majus L. Alkaloids (Ukrain). Journal of Cancer Research and Clinical Oncology,
SupplementVol.116,A3.118.10,1990.
(9) NowickyJW,LiepinsA,ZbrojaͲSontagW,StaniszewskiA,DanilosJ.Evaluationof
clinicalstudiesofUkrainincancerpatients.Art:Bar.206,Zona:BarcelͲfos,29ͲNovͲ
90,09:37:310.
(10) NowickyJW,StaniszewskiA,ZbrojaͲSontagW,SlesakB,NowickyW,HiesmayrW.
EvaluationofThiophosphoricacidalkaloidderivativesfromChelidoniumMajusL.
(''Ukrain'') as an immunostimulant in patients with Various Carcinomas. Drugs
Exptl.Clin.Res.,XVII(2)139,1991.
(11) NowickyJW,LiepinsA,SlesakB,StaniszewskiA,HarlozinskaͲSzmyrkaA,ZbrojaͲ
Sontag W, Danilos J. Evaluation of clinical studies of Ukrain in cancer patients.
JournalofChemotherapy,Supplementn.4,522,1991.
(12) LiepinsA,NowickyJW.UkrainisSelectivelyCytostaticand/orCytotoxictoHuman
TumorandHIVͲInfectedCellsbutnottoHumanNormalCells.RecentAdvancesin
Chemotherapy, Anticancer Section, Proceedings of the 17th International
CongressofChemotherapy,Berlin,2660,1991.
61
(13) Vatanasapt V, Wongpratoom W, Mairiang P, Mairiang E, Chaiyakam C,
Buddhisawasd V, Pairojkul C, Nowicky JW. Preliminary report on clinical
experience in the use of Ukrain. Thai Cancer Journal, Volume 17 No. 1Ͳ2, 20,
1991.
(14) Nowicky JW, Liepins A, Staniszewski A, Slezak B, Nowicky W, Hiesmayr W. The
malignotoxicandimmunemodulatingpropertyofthealkaloidderivativeUkrain.
Journal of Cancer Research and Clinical Oncology, Suppl. Vol. 118, V1. 09. 05,
1992.
(15) Kleinrok Z, JagielloͲWojtowicz E, Matuszek B, Chodkowska A. Basic Central
Pharmacological Properties of Thiophosphoric acid alkaloid derivatives from
ChelidoniumMajusL.Pol.J.Pharmacol.Pharm.,Vol.44,227,1992.
(16) Remiszewska M, Wutkiewicz M, Jastrzebski Z, CzyzewskaͲSzafran H, Danysz A.
Pharmacological Effects of Ukrain in Rats and Rabbits. Acta Poloniae
PharmaceuticaͲDrugResearch,Vol.49no.4,43,1992.
(17) Liepins A, Nowicky JW. Activation of Spleen Cell Lytic Activity by the Alkaloid
Thiophophoric Acid Derivative: Ukrain. International Journal of
Immunopharmacology,14,8,1437Ͳ1442,1992.
(18) Slesak B, Nowicky JW, Harlozinska A. In Vitro Effects of Chelidonium Majus L.
Alkaloid Thiophosphoric Acid Conjugates (Ukrain) on the Phenotype of Normal
HumanLymphocytes.DrugsExptl.Clin.Res.,XVIII,17,1992.
(19) Chlopkiewicz B, Marczewska J, Ejchart A, Anuszewska E, Koziorowska J.
Evaluation of Mutagenic; Genotoxic and Transforming Properties of Ukrain.
DrugsExptl.Clin.Res.,XVIII,31,1992.
(20) Kleinrok Z, JagielloͲWojtowicz E, Nowicky JW, Chodkowska A, Feldo M.
Interaction between Ukrain and Aminophenazone in Analgesic Test in Rodents.
(21) Musianowycz J, Judmajer F, Manfreda D, Spängler P, Albrecht H, Hoffmann J,
MeijerD.ClinicalStudiesofUkraininTerminalCancerPatients(PhaseII).Drugs
Exptl.Clin.Res.,XVIII,45,1992.
(22) Danilos J, ZbrojaͲSontag W, Baran E, Kurylcio L, Kondratowicz L, Jusiak L.
Preliminary studies on the effect of Ukrain (Tris ^2Ͳ^>5BSͲ(5BA,6B, 12BA)@Ͳ
5B,6,7,12B,13,14ͲhexahydroͲ13Ͳmethyl>1,3@ benzodioxolo >5,6ͲC@Ͳ1Ͳ3Ͳdioxolo>
4,5,Ͳi@ phenanthriͲdiniumͲ6Ͳol]Ͳethaneaminyl` phosphinesulfide.6HCl) on the
immunological response in patients with malignant tumours. Drugs Exptl. Clin.
Res.,XVIII,55,1992.
(23) Wyczolkowska J, Czuwaj M, Maslinski C. The immunomodulating preparation
Ukraindoesnotinduceanaphylacticsensitizationinmiceandguineapigs.Drugs
(24) NowickyJW,ManolakisG,MeijerD,VatanasaptV,BrzoskoWJ.Ukrainbothasan
anticancerandimmunoregulatoryagent.DrugsExptl.Clin.Res.,XVIII,51,1992.
62
(25) Staniszewski A, Slesak B, Kolodziej J, HarlozinskaͲSzmyrka A, Nowicky JW.
Lymphocytesubsetsinpatientswithlungcancertreatedwiththiophosphoricacid
alkaloid derivatives from Chelidonium majus L. (Ukrain). Drugs Exptl. Clin. Res.,
XVIII,63,1992.
(26) Sotomayor E, Rao K, Lopez DM, Liepins A. Enhancement of macrophage
tumouricidalactivitybythealkaloidderivativeUkrain.Invitroandinvivostudies.
(27) Pengsaa P, Wongpratoom W, Vatanasapt V, Udomthavornsuk B, Mairieng E,
TangvorapongchaiV,PesiM,KrusanS,BoonvisootV,NowickyJW.Theeffectsof
thiophosphoricacid(Ukrain)oncervicalcancer,stageIBbulky.DrugsExptl.Clin.
Res.,XVIII,69,1992.
(28) LohningerA,HamlerF.ChelidoniummajusL.(Ukrain)inthetreatmentofcancer
patients.DrugsExptl.Clin.Res.,XVIII,73,1992.
(29) KleinrokZ,JagielloͲWojtowiczE,NowickyJW,ChodkowskaA,FeldoM,Matuszek
B. Some pharmacological properties of prolonged administration of Ukrain in
rodents.DrugsExptl.Clin.Res.,XVIII,93,1992.
(30) Juszkiewicz T, Minta M, Wlodarczyk B, Biernacki B. Teratological evaluation of
Ukraininhamstersandrats.DrugsExptl.Clin.Res.,XVIII,23,1992.
(31) JagielloͲWojtowiczE,KleinrokZ,SurmaczynskaB,BaranE,FeldoM,NowickyJW.
Effect of single and three months treatment with Ukrain on aminoͲtransferases
(ALTandAST)andontheserumproteinlevelinrodents.DrugsExptl.Clin.Res.,
XVIII,85,1992.
(32) JagielloͲWojtowicz E, Kleinrok Z, Nowicky JW, Matuszek B, Baran E,
Surmaczynska B. Effect of single and prolonged administration of Ukrain on
prolactinconcentrationinrats.DrugsExptl.Clin.Res.,XVIII,89,1992.
(33) JagielloͲWojtowicz E., Kleinrok Z., Matuszek B., Surmaczynska B., Baran E.,
Nowicky W., Nowicky J.W. Effect of three months treatment with Ukrain on
peripheralbloodmorphologyinrodents.DrugsExptl.Clin.Res.,XVIII,79,1992.
(34) JagielloͲWojtowiczE.,KleinrokZ.,FeldoM.,ChodkowskaA.,NowickyJ.W.Effect
of Ukrain on the efficacy of antiͲepileptic drugs against maximal electroshockͲ
inducedseizuresinmice.DrugsExptl.Clin.Res.,XVIII,107,1992.
(35) JagielloͲWojtowicz E., Kleinrok Z., Chodkowska A., Feldo M., Nowicky J.W.
Modification of antinociceptive action of morphine by Ukrain in rodents. Drugs
(36) Hohenwarter O., Strutzenberger K., Katinger H., Liepins A., Nowicky J.W.
SelectiveinhibitionofinvitrocellgrowthbytheantiͲtumourdrugUkrain.Drugs
(37) Danysz A., Kokoschinegg M., Hamler F. Clinical studies of Ukrain in healthy
volunteers(phaseI).DrugsExptl.Clin.Res.,XVIII,39,1992.
(38) BrüllerW.StudiesconcerningtheeffectofUkraininvivoandinvitro.DrugsExptl.
Clin.Res.,XVIII,13,1992.
63
(39) Nowicky J.W. Biological Properties of Ukrain in Experimental and Clinical
Investigations. International Medical Reviews, Avalanche Ltd. St. Petersburg,
Russia,1,1,5,1993.
(40) Nowicky J.W., Nowicky W., Liepins A. Cytostatic and cytotoxic effects of Ukrain
on malignant cells. VIII Mediterranean Congress of Chemotherapy, 24Ͳ29 May
1992, Athens, Greece, Journal of Chemotherapy, Supplement n. 1, Volume 5,
797,1993.
(41) NowickyJ.W.UkrainAntineoplasticImmunomostimulant.E09/029,NSCͲ631570,
NSCͲB238865, UKSRͲ222, W122, Drugs of the Future, Prous Science Publishers,
CopyrightProusScience,18(11),1015,November1993.
(42) Kamyshentsev M.V., Voltchek I.V., Btailovskaya I.V., Leschev A.L., Lavinsky Y.C.
andNowickyJ.W.TestingUkrainasanAntiͲInfluenzaRemedy.RecentAdvances
in Chemotherapy, American Society for Microbiology, Proceedings of the 18th
International Congress of Chemotherapy, Stockholm, Sweden, June 27ͲJuly 2,
645,1993.
(43) LiepinsA.,SotomayorE.M.,LopezD.M.andJ.W.Nowicky.BiologicalResponseͲ
Modifying Properties of the Alkaloid Derivative Ukrain (NSC 631570). Recent
Advances in Chemotherapy, American Society for Microbiology, Proceedings of
the18thInternationalCongressofChemotherapy,Stockholm,Sweden,June27Ͳ
July2,783,1993.
(44) Nowicky J. W., Manolakis G., Meijer D., Vatanasapt V., Brzosko W.J. and
Lohninger A. Immunological and Tumoricidal Properties of Ukrain. Recent
July2,793,1993.
(45) LohningerA.,MusianowycJ.,JudmaierF.,ManfredaD.,SpänglerP.,AlbrechtH.,
HoffmannJ.andMejerD.ResultsofPhaseIIClinicalStudieswithUkrain.Recent
July2,794,1993.
(46) Voltchek I.V., Nowicky J.W., Zolotukhin N.N., Kamyshentsev M.V.,
MiroshnichenkoA.G.,LeschevA.L.andBelskikhA.N.SomeImmunohematological
Effects of Ukrain. Recent Advances in Chemotherapy, American Society for
Microbiology,Proceedingsofthe18thInternationalCongressofChemotherapy,
Stockholm,Sweden,June27ͲJuly2,798,1993.
(47) Nowicky Jaroslaw W., Markowska Janina and Brzosko Witold J. Ukrain and
Natural Killer Cells. Recent Advances in Chemotherapy, American Society for
Microbiology,Proceedingsofthe18thInternationalCongressofChemotherapy,
Stockholm,Sweden,June27ͲJuly2,863,1993.
(48) ZemskovV.S.,YaremchukO.Ya.,SusakYa.M.,DenekaE.R.,KravchencoO.V.and
KamenetsL.Ya.ExperienceoftheApplicationofUkraininOncologicalPracticein
Ukraine.RecentAdvancesinChemotherapy,AmericanSocietyforMicrobiology,
Proceedings of the 18th International Congress of Chemotherapy, Stockholm,
Sweden,June27ͲJuly2,870,1993.
64
(49) Nowicky J.W., Cisak E., Liepins A., Susak Ja.M., Semskow W. Stimulation of
phagocyticactivityinvitro,invivoandintheclinicbyUkrain.11thFutureTrends
in Chemotherapy, Interdisciplinary World Congress on Antimicrobial and
Anticancer Drugs, 24Ͳ27 April 1994, Palexpo Geneva (Switzerland), Abstracts:
abs.68,April1994.
(50) KurikM.V., SusakY.M., KravchenkoO.V. SomebiophysicalpropertiesofUkrain.
11th Future Trends in Chemotherapy, Interdisciplinary World Congress on
Antimicrobial and Anticancer Drugs, 24Ͳ27 April 1994, Palexpo Geneva
(Switzerland),Abstracts:abs.79,April1994.
(51) LisnyakO.I.,LozjukR.M.Biologicalactivityofsomethiophosphamidederivatives
ofalkaloidswithrespecttoinfluenzavirus.11thFutureTrendsinChemotherapy,
Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs, 24Ͳ27
April1994,PalexpoGeneva(Switzerland),Abstracts:abs.96,April1994.
(52) Lozjuk R.M., Lisnyak O.I., Lozjuk L.V. Theoretical grounds and experimental
confirmationofantiviraleffectofthepreparationUkrain.11thFutureTrendsin
Chemotherapy,InterdisciplinaryWorldCongressonAntimicrobialandAnticancer
Drugs,24Ͳ27April1994,PalexpoGeneva(Switzerland),Abstracts:abs.95,April
1994.
(53) Brzosko W.J., Graczyk A., Konarski J., Nowicky J.W. Synergic influenceof Ukrain
and protoporphyrine amino conjugates on human malignant cell lines. 11th
Future Trends in Chemotherapy, Interdisciplinary World Congress on
Antimicrobial and Anticancer Drugs, 24Ͳ27 April 1994, Palexpo Geneva
(54) BrzoskoW.J.,UglianicaK.,FominK.,NowickyJ.W.InfluenceofUkrainonbreast
cancers.11thFutureTrendsinChemotherapy,InterdisciplinaryWorldCongress
on Antimicrobial and Anticancer Drugs, 24Ͳ27 April 1994, Palexpo Geneva
(55) ZemskovV.S.,SusakYa.M.,ZemskovS.V.Ukrainmonotheraphyfortreatmentof
colorectal cancer. 11th Future Trends in Chemotherapy, Interdisciplinary World
Congress on Antimicrobial and Anticancer Drugs, 24Ͳ27 April 1994, Palexpo
Geneva(Switzerland),Abstracts:abs.78,April1994.
(56) LiepinsA.,NowickyJ.W.Selectiveinductionofprogrammedcelldeath(apoptosis)
in malignant cells by the alkaloid derivative Ukrain (NSCͲ613570). 11th Future
TrendsinChemotherapy,InterdisciplinaryWorldCongressonAntimicrobialand
Anticancer Drugs, 24Ͳ27 April 1994, Palexpo Geneva (Switzerland), Abstracts:
abs.93,April1994.
(57) JagielloͲWojtowiczE.,KleinrokZ.,NowickyJ.,HodkowskaA.,FeldoM.,Matuszek
B.,JablonskaM.,GorzelakM.EffectofsixmonthtreatmentwithUkrainonearly
osteoporosis induced by ovariectomy in rats. 11th Future Trends in
Chemotherapy,InterdisciplinaryWorldCongressonAntimicrobialandAnticancer
Drugs,24Ͳ27April1994,PalexpoGeneva(Switzerland),Abstracts:abs.49,April
1994.
65
(58) Nowicky J.W., Wladyslawa Nowicky, Hiesmayr W., Potopalsky A.. Alterations of
DNA;RNAandproteinsynthesisinmalignantcellsundertheinfluenceofUkrain.
XVI International Cancer Congress 1994, 30 October Ͳ 5 November 1994, New
Delhi,India,abs.PSB15Ͳ17,319.
(59) VoltchekI.UkrainͲDrugoftheFutureintheCancerTreatment?TerraMedica,
Nr.1,1995,24Ͳ25(inRussian).
(60) Ciebiada I., Korczak E.,Denys A., Nowicky J. W. Effect of Ukrain preparation on
immuneresponseinmiceaffectedbyinfluenzavirus.JournalofChemotherapy,
Vol.7(Suppl.),n.4,1995101Ͳ104.
(61) VoltchekI.,KamyshentsevM.,LavinskyY.,NowickyJ.,MedvedevY.,LitvinchukL.
Comparative Study of the Cytostatic Effects of Oliphen and Ukrain. Journal of
Chemotherapy,Vol.8Ͳn.2,1996,144Ͳ146.
(62) Liepins A., Nowicky J.W., Bustamante J.O., Lam E. Induction of Bimodal
Programmed Cell Death in Malignant Cells by the Derivative Ukrain (NSCͲ
631570).DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,1Ͳ7.
(63) Nowicky JW, Hiesmayr W, Nowicky W, Liepins A. Influence of Ukrain on DNA,
RNAandProteinSynthesisinMalignantCells.DrugsExptl.Clin.Res.,XXII(Suppl.),
1996,9Ͳ19.
(64) Nowicky J.W., Hiesmayr W., Influence of Ukrain on Human Xenografts in vitro.
DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,21Ͳ25.
(65) JinY.M.,NowickyJ.W.,LiepinsA.MitogenicPropertiesofUkrain(NSCͲ631570)on
HumanPeripheralBloodMonocytes:ClinicalImplications.DrugsExptl.Clin.Res.,
Vol.XXII(Suppl.),1996,27Ͳ30.
(66) Liepins A., Nowicky J.W. Modulation of Immune Effector Cell Cytolytic Activity
andTumourGrowthInhibitioninvivobyUkrain(NSCͲ631570).DrugsExptl.Clin.
Res.,Vol.XXII(Suppl.),1996,31Ͳ42.
(67) Susak Y.M., Zemskov V.S., Yaremchuk O.Y., Kravchenko O.B., Yatsyk I.M., Korsh
O.B.ComparisonofChemotherapyandXͲrayTherapywithUkrainMonotherapy
forColorectalCancer.DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,43Ͳ50.
(68) UglanicaK.N.,FominK.A.,NefyodovL.I.,NowickyJ.W.,BrzoskoW.J.,Jankowski
A. Influence of Ukrain on Patients with Surgically Treated Breast Cancer
(IntroductoryRemarks).DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,51Ͳ54.
(69) Brzosko W.J, Uglanica K.N., Fomin K.A., Nowicky J.W. Influence of Ukrain on
BreastCancer.DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,55Ͳ62.
(70) UglanicaK.N.,FominK.A.,NefyodovL.I.,NowickyJ.W.,BrzoskoW.J.,Jankowski
A. Influence of Ukrain on Patients with Surgically Treated Breast Cancer. Part I.
Clinical and Laboratory Parameters. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.),
1996,63Ͳ66.
(71) UglanicaK.N.,FominK.A.,NefyodovL.I.,VilkiewichT.W.,NowickyJ.W.,Brzosko
W.J.,JankowskiA.InfluenceofUkrainonPatientswithSurgicallyTreatedBreast
Cancer.PartII.HormonalProfile.DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,
67Ͳ70.
66
(72) Uglanica K.N., Fomin K.A., Nefyodov L.I., Djurd T.I., Nowicky J.W., Brzosko W.J.,
Jankowski A. Influence of Ukrain on Patients with Surgically Treated Breast
Cancer. Part III. The Immune System. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.),
1996,71Ͳ74.
(73) UglanicaK.N.,MaciukJ.R.,FominK.A.,NefyodovL.I.,KravchukR.I.,Vinogradova
L.M.,NowickyJ.W.,BrzoskoW.J.InfluenceofUkrainonPatientswithSurgically
TreatedBreastCancer.PartIV.ElectromicroscopicandCytochemicalEvaluation.
(74) NefyodovL.I.,UglanicaK.N.,SmirnovV.Y.,DoroshenkoY.M.,FominK.A.,Nowicky
J.W.,BrzoskoW.J.AminoAcidsandTheirDerivativesinBloodPlasmaofPatients
withBreastCancerTreatedwithUkrain.PartV.DrugsExptl.Clin.Res.,Vol.XXII
(Suppl.),1996,83Ͳ86.
J.W., Brzosko W.J. Amino Acids and Their Derivatives in Tumour Tissue from
PatientswithBreastCancerTreatedwithUkrain.PartVI.DrugsExptl.Clin.Res.,
(76) Nowicky J.W., Hiesmayr W., Liepins A. Influence of Ukrain on Immunological
Blood Parameters in vitro and in vivo. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.),
1996,91Ͳ94.
(77) BoykoV.N.,VoltchekI.V.,PetrovA.S.,BubnovV.P.ActionofUkrain,aCytostatic
and Immunomodulating Drug, on Effects of Irradiation. Drugs Exptl. Clin. Res.,
(78) JagielloͲWojtowicz E., Kleinrok Z., Nowicky J.W., Jablonski M., Gorzelak M.,
Chodkowska A., Feldo M., Matuszek B. Effect of SixͲMonth Treatment with
UkrainonEarlyOsteoporosisInducedbyOvariectomyinRats.PartI:Preliminary
StudiesofBoneParameters.DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,101Ͳ
104.
(79) JagielloͲWojtowicz E., Kleinrok Z., Nowicky J.W., Chodkowska A., Feldo M.,
SurmaczynskaB.,GorzelakM.,JablonskiM.EffectofSixͲMonthTreatmentwith
UkrainonEarlyOsteoporosisInducedbyOvariectomyinRats.PartII:Preliminary
StudiesofPeripheralBloodParameters.DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),
1996,105Ͳ108.
(80) JagielloͲWojtowicz E., Kleinrok Z., Nowicky J.W., Baran E. Effect of SixͲMonth
Treatment with Ukrain on Early Osteoporosis Induced by Ovariectomy in Rats.
PartIII:PreliminaryStudiesofSomeHormoneLevels.DrugsExptl.Clin.Res.,XXII
(Suppl.),1996,109Ͳ113.
(81) Susak Y.M., Kurik M.V., Kravchenko O.V., Zemskov S.V. Certain Biophysical
PropertiesofUkrain.DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,113Ͳ116.
(82) Zhalilo LI, Susak YM, Zemskov SV, Susak IA. Influence of Ukrain on the Redox
Processes of Hepatocytes. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 117Ͳ
120.
67
(83) BrzoskoW.J.,GraczykA.,KonarskiJ.,NowickyJ.W. SynergicInfluenceofUkrain
and protoporphyrin Amino Acids Conjugates on Human Malignant Cell Lines.
(84) Wyczólkowska J., Michon T., Nowicky J.W. Inhibitory Effect of Thiophosphoric
Acid Alkaloid Derivatives from Chelidonium majus L. (Ukrain) on Ovalbumin
AntigenicityandAntiovalbuminIgEAntibodyResponseinMice.DrugsExptl.Clin.
(85) JagielloͲWojtowicz E., Kleinrok Z., Chodkowska A., Nowicky J.W., Piper H.,
KubiatowskiT.AntinociceptiveEffectofTenDayAdministrationofUkraininMice
andInteractionoftheTreatmentwithMorphine.DrugsExptl.Clin.Res.,Vol.XXII
(Suppl.),1996,129Ͳ132.
(86) JagielloͲWojtowiczE.,KleinrokZ.,NowickyJ.W.,ChodkowskaA.,KubiatowskiT,
PiperH.InteractionBetweenUkrainandMorphineinTheirTenͲDayTreatmentin
Mice in the Writhing Syndrome Test. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.),
1996,133Ͳ134.
(87) CiebiadaI,KorczakE.,NowickyJW,DenysA.DoestheUkrainPreparationProtect
Mice Against Lethal Doses of Bacteria? Drugs Exptl Clin Res, XXII (Suppl), 1996,
135Ͳ140.
(88) Lozjuk R.M., Lisnyak O.I., Lozjuk L.V. Theoretical Grounds and Experimental
ConfirmationoftheAntiviralEffectofthePreparationUkrain.DrugsExptl.Clin.
(89) CiebiadaI.,KorczakE.,NowickyJ.W.,DenysA.EstimationofDirectInfluenceof
Ukrain Preparation on Influenza Viruses and the Bacteria E. coli and S. aureus.
(90) Lisnyak OI, Lozjuk RM. Biological Activity of Some Thiophosphamide Derivatives
ofAlkaloidswithRespecttoInfluenzaVirus.DrugsExptl.Clin.Res.,XXII(Suppl.),
1996,153Ͳ156.
(91) StabucB.,BenedicicD.UkrainwithChemotherapyinMalignantMelanoma(Case
Report).DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,159Ͳ162.
(92) HamlerF.,HiesmayrW.,KorshO.B.,MelnykA.UkrainMonotherapyinMalignant
Melanoma (Case Report). Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 163 Ͳ
166.
(93) KotsayB.,LisnyakO.,MyndiukO.,RomanyshynJ.,FabriO.UkrainTreatmentof
Rhabdomyosarcoma (Case Report). Drugs Exptl. Clin. Res., Vol. XXII (Suppl.),
1996,167Ͳ170.
(94) Kadan P., Korsh OB, MelnykA. Ukrain Therapy of Recurrent Breast Cancer with
Lung Metastases (Case Report). Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996,
171Ͳ174.
(95) NowickyJ.W.,SchrammE.,GodyshY.BiophysicalEffectsofUkrainTherapyina
PatientwithBreastCancer(CaseReport).DrugsExptlClinRes.,VolXXII(Suppl),
1996,175Ͳ182.
68
(96) Kroiss T., Melnyk A., Korsh O.B. Ukrain Treatment in Carcinoma of the Cervix
(CaseReport).DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,183Ͳ186.
(97) Lohninger A, Korsh OB, Melnyk A. Combined Therapy with Ukrain and
ChemotherapyinOvarianCancer(CaseReport).DrugsExptl.Clin.Res.,Vol.XXII
(Suppl.),1996,187Ͳ190.
(98) Sakalo V.S., Korsh O.B., Melnyk A. Ukrain Treatment in a Patient with NonͲ
SeminomatousGermͲCellTumourofTestis(CaseReport).DrugsExptl.Clin.Res.,
(99) Vyas J.J., Jain V.K. Ukrain Treatment in Carcinoma of the Oesophagus (Case
Report).DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,195Ͳ198.
(100) KadanP.,KorshO.B.,HiesmayrW.UkrainintheTreatmentofUrethralRecurrent
Carcinoma (Case Report). Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 199 Ͳ
202.
(101) Steinacker J., Kroiss T., Korsh O.B., Melnyk A. Ukrain Treatment in a Frontal
AnaplasticGradeIIIAstrocytoma(CaseReport).DrugsExptl.Clin.Res.,Vol.XXII
(Suppl.),1996,203Ͳ206.
(102) SteinackerJ.,KorshO.B.,MelnykA.UkrainTherapyofaRecurrentAstrocytoma
oftheOpticNerve(CaseReport).DrugsExptl.Clin.Res.,Vol.XXII(Suppl.),1996,
207Ͳ210.
(103) Voltchek I.V., Liepins A., Nowicky J.W., Brzosko W.J. Potential Therapeutic
Efficacy of Ukrain (NSC 631570) in AIDs Patients with Caposi’s Sarcoma. Drugs
Exptl.Clin.Res.,Vol.XXII(Suppl.),1996,211Ͳ214.
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