February 1 - 4. 20lCt f" f Ji. U A �i·

Under the Patronage of . . Stl ikh Nahayan Mabarak AI Nahayan

Minister of Higher Education and Scientific Research Chancellor, Higher Colleges of Technology

Abstracts

C O RGANI ZER S ) HI�HER II... 'E k a COllEGE S OF '\ U re TECHNOlOGV ) Sdcmclll.:ld,

II

186 Posters

activity. Ayurveda with its holistic approach visualized the control of infections also by other mechanisms such as alternation in the host's physiology . The current study substantiates this hypothesis using hot water extract of P gua/ava (guava) leaves for the treatment of diarrhoeal diseases which account for nearly 3 2 % of all deaths globally . Whilst, the guava leaf extract was not bactericidal for diarrhoeagenic £. coli it exerted its effect by preventing colonization of the gut as measured by adherence to and invasion of Hep-2 cells. It also decreased the production of the heat labile toxin and its b inding to GMI. Since this form of treatment targets both host and parasite, development of drug I·esistance would be minimized.

PO-84

ANTICATAI�ACT ACTIVITY OF BAUHINIA VAIUEGATA DARK EXTRACT

Surendra H. I30dakhe and Alpana Ram

Reader III PllOrll/aeology SLT Inslilule of Pharm. Sciences, G. G.Universily. BILASPUI? (Chhatllsgarir;. India. bodvas@redi/!iIlUilcoll1

Bauhlnia varlegala is traditionally used in the eye diseases. In this invest i gation anticataract activity was detemlined using cataract formation in developing chick embryo by hydrocortisone. Lenses were evaluated firstly for extent of opacity and secondly, for lens g lutathione (GSH) levels. Bauhinia variegClta bark was collected. authenticated, air dried and extracted with ethanol in Soxhlet apparatus. Fourteen days old Austra lol'p fertilized eggs were divided into different groups of six eggs each. After 24 hrs incubntion in a hUl11idified incubatol (370q, ill 15 days of age; hydrocortisone (0.2SfIM/O.2ml/egg) was adillin istered 10 the chorioa llantoic membrane of chick embryos through a smal l hole in the egg shell on the air sack. Ascorbic acid (standard) or B varlegala extract (test) were administered at 3, 10 and 20 hI' afler hydrocortisone administration at specified dose. The puncture was sealed with a cellophane tape and eggs were incubated fLX 48 Ins in il humidified incub<llor at 37°C. After 48 hrs the lenses were isolated for the detel' l1l ination of the extent llf opacit), and G lutathione level. The extl'act prevented the opacif'ication of the

chick embryo lenses induced by hydrocortisone. The extract also prevented the dec l ine of GSH content caused by hydrocortisone. The results indicate that B. varlegata bark extract protect the cataract formation caused by hydrocortisone in ch ick embryos in concentration dependent manner.

PO-lOl

RETROSPECTIVE ANALYSIS OF COMPLEX TREATMENT OF PATIENTS WITH RECTAL CANCER

A.V. I3orot;], A. W. Nowicky and A.A. I3orota

Deparll1ll!lIl oj f'meralogl'. Donelsk I?egionol ,jnli,Cancer Cenler (lvborolcd'?,lIkr.nel

We perfclIl11e'ti � ranu oill ized investigation of clinical efficacy of newly produced anticancer dnlg Ukrain. which is chnraclerized like a potent il11nlllnolllodulating and ulncel'-suppress ing agent.

In the course of ill l est i gation we cOIll Jl<Hed two idell ticill groups of RC-patients, each cOlllprised 2,1 pcoples. Pat IClliS of" the I group I·eceived Ukrain in dose of' 60 I11g iiI' before surg ical intefl'elltlon. then operotlon II<1S I lcl f'or llled, after thill Clnothel· dose of Ukrain (40 I11g i/v) lI'as repe atcc l ly injected Patients 01

thc II gloup IIe're: IIiHit'lwent to aitelllative (traditional) scheme of treatment: administl·C1ti on of' 5-fluorufilC,1

(5000 l11g) ill combination with the course of radial therClp) (25 Gr) WClS followed b) sUI'gicill intervenllOl1.

thcn ,-nuoruraCl I (5000 Illg) was injected again. Patienls of the I group was round to be i ll Lletter clinical

state COUISe (,r nOIJ-(Ici.lllV(lnt cllenlotherClpy led to il11prol ' ing as general state or pat i ellts, as paralueters (,I theil il11J1IUIJ()I(I�lcal ,tdtU\ (lgA. IgM, IgG, T- B- I) · ll1phocytes . pl1i1goc),tic activily: ell': /11;1) C'[,\)

l(ddic;II'III�i\"dl illtc:ncntILlns-rcscction uf'the (CClllll1 111 differ-cnt mod ificat ion 11'10110 perf"orl11eci t,l patie!l!;

1) l lwtl1 �1\'III)' C'UI,c: of Illhtopcr;ltll c pcriod prol':u to be l110rc filvLlralJlt' ill patienls ul' the I grl'IIP, (\:C:lllrc·IILC' "I !l,"I<'pc:r,lllle (lllllplictitiollS (purulcllt-iliflalllllldtlH) ill I11clin) cilnstillited S .. �"() ill I JnJ

ltJ.:"'" ;;i :: .,::i\<:i� ,.� i�;:::�:;!� P�"'��i;()Jl/ ... '�·1 !"·,:-st!!r� IlfC(\llll"d�"'\ fre;lllllt."Jlr (lr·I<'C-p;lfi(�!lt� \\('rc Illllrc I(lYl1f;-lbl .. · , '" h 'I.' i. �'I, " "" I " , . I , I · I "Ill C h(' I)) () I herilll \ ,I S \1 c·lI. I � -I ems sur I I I ill ill pat iClllS ,) I' (/ I e I '-' I'LlU j1 \I �l \ :h I IIllel! ."

-,"" t(, j'.III'llh dlc·tll. III patlelll, ,)Itht' I I glLluj1 - -1.'.811 .. t I � pil[lents ciied)

�chanislllS hot Water

arly 3.2% E coli il of Hep.2

s form of

/1). India

iv iry \Vas �valuated bark \\las

days old lIioll ill a slered to air sack. hr after

and eggs d for the )11 of the

COlltellt )rll1atiOIJ

ECTAL

Ukrilin,

ised 2:1

In. thell iellts of

Ir'lIr,lC) ! 'enriorl. clinical

;ler'S of

group

I ,Hid

.'rahle'

lell .'IS

�t mational Conference on Drug Discovery and Therapy I In e

187

I conclusions: Complex therapy. which is based on Ukrain ildminislration in neo-adjuvant regimen allowed

10 improve both direct (lnd postponed results of trearment of I�C-pati ents

,

eQ£ /1 INTERLEUKIN- I I THERAPY AS A REPLACEMENT FOR [VIG?

I)allila Leontyev, Yulia Katsman and Donald R. Branch

f I I

Research & Development, Canadian Blood Services, Ottawa, Of/torio, Canada donbral1ch(iijuloronloc(I

I

Intravenolls immunoglobulin (IVIG) is a pleiotropic ther-apeutic, used to treat il num ber of imlllunologic,

autoimmune and inflammiltory conditions. IVIG is produced fj-om lhousands of humiln plasma donors,

requires high doses for efficacy, is very expensive and has some problematic side effects, including a slighl

risk of disease transmission. Although the mechanism or action of IVrG is uncertain. we have recently

proposed that IVIG effects can be explained by its ability to induce interlcukin (fL)-1 I. IL-II is a pleiotropic c)'lokine that has been used to treat a similar spectrum of disorders as has IVrG. Thus, use of IL-I I Illay provide a replacement drug for IVIG. However, we have found that the expression system used for production of recombinant IL-II (riL-II) may affect its /11 VIVO efficacy. Indeed, we have shown using a mouse model, decreased efficacy of rfL-11 to reverse immune thrombocytopenia when using rlL-11 produced in Esherichia coli compared to rlL-11 produced in Baculovirus. Thus, riL-11 efficacy may be dependent on the in vitro expression system used to produce it. It is thus imperative that any future clinical trials of riL-11 should take into consideration the manufacturing process lIsed to produce the drug in any evaluation of ef'fic(lCY· In this regard, our mouse model may be of benefit in evaluation ol-IL-II efficacy for human use.

I

PO-59

PENTOXIFY LLINE - A NOVEL TREATMENT FOR SPUR CELL HAEMOLYTIC ANAEMIA COMPLICATING ALCOHOLIC CIRRHOSIS

M.A. Butt, D.1. Ismflil, L.T.H. Pee, A. Owolabi and A.J.K. Piotrowicz

Deptlr/menl o/Caslroel1ler% gy. Queen Elizabelh Ihe Queell Mother Hospila/, UK. adilbllll@doclor:"org Ilk

Spur cel l haemolytic anaemia is a rare complication of alcoholic cirrhosis and generally carries a poor prognosis. The only definitive cure reported in the literature is liver transplant. In the United Kingdom, patients with severe alcoholic cirrhosis have to be abstinent from alcohol for at least 6 months prior to consideration of liver transplantation.

We report on the successful use of pentoxifylline in a 4J-year-old man who presented with decompensated alcoholic cirrhosis with alcoholic hepatitis and spur cell haemolytic anaem ia. Initial treatment with steroids controlled the hepatitis but not the haemolytic anaemia. The addition of pentoxifylline successfully treated the haemolysis for 3 '/, months judged by a significant reduction in trnnsfusion requirements. Unfortunately, he rapidly deteriorated and died from sepsis with multi-organ failure following this period.

Only one other study in the litel'ature has used pentoxifylline for this condition but in combination with tlunarizine and cholest)'ramine. We report the first use of pentoxifylline as the sole pharmacological agent to treat this rare hileillolytic complication and highlight its potential to act as a bridge to liver transplantation in patients not initiilily meeting liver ITilnsplall1 criter·ia.

PO-50

ULTRASONIC LOADING TECHNIQUl': FOR CANDESARTAN HAS BETTER EFFICIENCY THAN IONIC Gt:LLATiOi�

A. Geccr, N. Y ild iz, B. Tliran ;)nd A. Calindi

Depllrlllleill a/Chemica/ Eligineenllg, Focilill' ()jElIgII1C'Cl'lllg, .111/.:(11'(1 Ulliven·lly. fllr/.:e)' ca/illilii'ii]ellg (fllko/D.edll.lr

An antihypertensive dnlg c(/l/(/esar{()I7(C'Ii-l!oNr,01) was loaded to trimethyl chitosiln nanopanicles by ionic ::',ellation[ I! ilnd ultras(1nic efTect[2]lechlliqucs. The efficicncies of cUlldesartan loading were cOIllPQred fm

DRUGS EXPTl. CLiN. RES XXIV (5/6) 221-226 (1998)

COMPARATIVE EVALUATION OF THE COMPLEX TREATMEN T OF RECTAL

CANCER PATIENTS (CHEMOTHERAPY AND X-RAY THERAPY,

UKRAIN MONOTHERAPy)

BONDAR G.v., BOROTA A.V., YAKOVETS Y.I., ZOLOTUKHIN S.E.

Donetsk Regional Anti-Cancer Center, Donetsk, Ukraine.

Summary: A total of 48 patients suffering from rectum cancer were included in this randomized study conducted at the Proctology Department of the Donetsk Regional Anti-Cancer Center. Patients in group I (24 patients) received an intensive course of high fractional X-ray therapy (cumulative dose up to 25 Gy) with direct protracted endolymphatic chemotherapy with 5-fluorouracil (5-FU) instilled in 600 mg/m2 each day before operation, up to a cumulative dose of 5 g. The 24 patients in group II were treated with Ukrain as monotherapy, 10 mg each second day before operation (up to a cumulative dose of 60 mg) and a total of 40 mg after surgical intervention. Repeated Ukrain courses (100 mg/per course) were also given 6 months after surgical operation. In each ease preoperative treatment was followed by routine surgical operation. Prolongation morbi were found to have developed 14 months later in six patients in group I (25.0%), whereas in group II they were found only in two cases (8.3%). Comparative investigation of objective and subjective signs, analysis of results of instrument and X-ray data, as well as dynamic study of the histological structure of rectal tumors, indicate that Ukrain exerts a more potent malignotoxic and immunomodulating action than other types of anticancer treatment.

Introduction

The unsatisfactory results of 5-fluorouracil (5-

FU) application for the treatment of colorectal can­

cer patients as well as its high toxicity drives the

search for new, more effective remedies (1,2). The

chelidonin thiophosphoric acid derivative Ukrain

(USA patent No. 4.970.212, 1990) seems to be a

Address lor correspondence: AV Borola, Donelsk RegIonal

Anli-Cancer Cenler, Poiolskaya Sir. 2-A. Donelsk, 340092,

Ukraine.

0378-6501/98/5/6/000221 + 6 $02.50/0

promising agent for the treatment of colorectal can­

cer. The special immunological activities of Ukrain

(NSC-631570) have been demonstrated not only in vitro (3-8), but also in vivo and in clinical studies (9-

13). The malignotoxic properties of Ukrain have

been tested on different cancer cell culture lines,

i.e., EORTC, the Netherlands: E901029, W122,

UKRS-22; NSC-62388657 National Cancer

Institute, USA NSC: 63 1570-W/1 (14, 15). In addi­

tion, Nowlcky et al. have reported increased tumo­

ricidal action of Ukrain on murine adenocarcino­

mas (11).

© 19913 Bioscience Ediprinl litc 221

222

Bondar G.V. et al.

Comparative assessment carried out at the

National Cancer Institute (Bethesda, Maryland,

USA) revealed that the cytotoxic effect exerted by

Ukr'-ain upon human colon carcinoma cell culture

lines (Cola 205, DLD-1, HCC-2998, HTC-116,

HT29, KM12, KM20L2, SW620) was 100-fold high­

er than the cytotoxic eHect of routinely used 5-FU

(13). As was pOinted out in the EORTC study, the

colorectal cell line CXF displays high sensitivity to

toxic Ukrain action. The malignotoxic properties of

Ukrain in vitro are now undoubted, but special

study of the correlation between the eHects of

Ukrain in vitro and clinical experience needs to be

carried out. The purpose of this study was to inves­

tigate the above-mentioned problem and to evalu­

ate the eHicacy of Ukrain as a new potent drug in

the treatment of colorectal cancer.

It is quite understandable that any cytostatic

drug exerting malignotoxic action inevitably leads

to general toxic action and immune system sup­

pression in colorectal cancer patients, Oncologicat

therapy would ideally require maximum toxicity

against tumor cells and minimal toxicity to the

organism. Special attention has been drawn to the

stimulation of the immune system. Ukrain seems to

be a good combination of the above-mentioned

properties (12). In this study, based on clinical

observation, we tried to estimate the therapeutic

possibilities of Ukrain in the treatment of a severe

disease like colorectal cancer, in comparison with

traditionally used radiation therapy and endolym­

phatic chemotherapy with 5-FU.

Patients and methods

A total of 48 patients (30 men and 18 women)

suffering from rectal cancer or who had been treat­

ed at the Proctology Department of the Donetsk

Regional Anticancer Center were enlisted in a ran­

domized study which was approved by the Ethics

Commission of the Center. The patients' ages

ranged from 36-66 years, the mean value was 56.3

years. The experimental groups were made up of

patients with rectal tumors corresponding to T3-

4NOMO and T3-4N1-3MO stages of TNM classifica­

tion without severe accompanying disease or com­

plications of the basic process. Histological verifi­

cation of tumors carried out in each case before

starting the special treatment revealed adenocarci­

nomas at different degrees of diHerentiation in

89.7% of cases.

All patients were subdivided into two random­

ized groups. Patients in group I (n=24) received a

preoperative intensive course of high-fractional X­

ray therapy (6 Gy daily, up to 25 Gy) with direct

endolymphatic chemotherapy with 5-FU (600

mg/m2 daily), up to a cumulative dose of 5 g. After

preoperative treatment all patients underwent a

surgical operation. Group II comprised 24 patients

who received monotherapy with Ukrain (Nowicky

Pharma, Vienna, Austria): i. v. injections of 10 mg

each second day before surgical operation (up to

60 mg cumulative dose) and a total of 40 mg dur­

ing the postoperative period. Additional repeated

courses (100 mg Ukrain per course) were per­

formed 6 months after surgical intervention.

Only patients without verified distant metas­

tases were included in the randomized study.

Metastatic invasion into regional lymphatic glands

was found in 56.3% of cases (Table I). Where nec­

essary, patients received corrective infusion, car­

diotropic and general reinforcement therapy.

The complex preoperative study involved the

determination of tumor dimensions and mobility,

general and biochemical analysis of the blood and

urine, assessment of immune status (T- and B-Iym­

phocytes count, concentrations of immunoglobu­

lins A, M, G; plasma content of the circulating

immune complexes (CIC) and phagocytic activity

of neutrophils). In addition, the immune-enzymatic

method was used to determine the blood content of

222

Bondar G.V. et al.

Comparative assessment carried out at the National Cancer Institute (Bethesda, Maryland , USA) revealed that the cytotoxic effect exerted by Ukrain upon human colon carcinoma cell culture lines (Cola 205, DLD-1, HCC-2998, HTC-116, HT29, KM12, KM20L2, SW620) was 100-fold high­er than the cytotoxic effect of routinely used 5-FU (13). As was pointed out in the EORTC study, the colorectal cell line CXF displays high sensitivity to toxic Ukrain action. The malignotoxic properties of Ukrain in vitro are now undoubted, but special study of the correlation between the effects of Ukrain in vitro and clinical experience needs to be carried out. The purpose of this study was to inves­tigate the above-mentioned problem and to evalu­ate the efficacy of Ukrain as a new potent drug in the treatment of coloreclal cancer.

It is quite understandable that any cytostatic drug exerting malignotoxic action inevitably leads to general toxic action and immune system sup­pression in colorectal cancer patients. Oncological therapy would ideally require maximum toxicity against tumor cells and minimal toxicity to the organism. SpeCial attention has been drawn to the stimulation of the immune system. Ukrain seems to be a good combination of the above-mentioned properties (12). In t/lis study, based on clinical observation, we tried to estimate the therapeutic possibilities of Ukrain in the treatment of a severe disease like colorectal cancer, in comparison with traditionally used radiation therapy and endolym­phatic chemotherapy with 5-FU.

Patients and methods

A total of 48 patients (30 men and 18 women) suffering from rectal cancer or who had been treat­ed at the Proctology Department of the Donetsk Regional Anticancer Center were enlisted in a ran­domized study which was approved by the Ethics

Commission of the Center. The patients' ages ranged from 36-66 years, the mean value was 56.3 years. The experimental groups were made up of patients with rectal tumors corresponding to T3-4 NOMO and T3-4N 1-3MO stages of TNM classifica­tion without severe accompanying disease or com· plications of the basic process. Histological verifi­cation of tumors carried out in each case before starting the special treatment revealed adenocarci­nomas at different degrees of differentiation in 89.7% of cases.

All patients were SUbdivided into two random­ized groups. Patients in group I (n=24) received a preoperative intensive course of high-fractional X­ray therapy (6 Gy daily, up to 25 Gy) with direct endolymphatic chemotherapy with 5-FU (600 mg/m2 daily), up to a cumulative dose of 5 g. After preoperative treatment all patients underwent a surgical operation. Group" comprised 24 patients who received monotherapy with Ukrain (Nowicky Pharma, Vienna, Austria): i.v. injections of 10 mg each second day before surgical operation (up to 60 mg cumulative dose) and a total of 40 mg dur­ing the postoperative period. Additional repeated courses ( 100 mg Ukrain per course) were per­formed 6 months after surgical intervention.

Only patients without verified distant metas­tases were included in the randomized study. Metastatic invasion into regional lymphatic glands was found in 56.3% 01 cases (Table I). Where nec­essary, patients received corrective infusion, car· diotropic and general reinforcement therapy.

The complex preoperative study involved the determination of tumor dimensions and mobility, general and biochemical analysis of the blood and urine, assessment of immune status (T- and B-Iym­phOCy1es count, concentrations of immunoglobu­lins A, M, G; plasma content of the circulating immune complexes (CIC) and phagocytic activity

of neutrophils). In addition, the immune-enzymatic method was used to determine the blood content of

Comparative evaluation of the complex treatment of rectal cancer patients

Table I Distribution 01 coloreclal cancer patienls according to TNM-classilicalion

TNM staging

T3NOMO T3NIMO T3N2MO T3N3MO T4NOMO T4N1MO T4N2MO T4N3MO Total

5-FU = 5-llurouracil

5-FU + X-ray therapy

2 2 1

3

8 1 3 4

24

a-fetal protein (AFP) and carcino-embryonal anti­

gen (CEA). Additional topographical data were

obtained by means of abdominal sonography and

computerized tomography. X-ray studies of the

lungs and other examinations were also per­

formed. Tumor dimensions, as measured by rec­

toscopy, fibroscopy and irrigoscopy, varied from

2.8±3.4 cm to 8.6±9.8 cm.

Results

After finishing the specific preoperative treatment

for each group, repeated dynamic followup exami­

nations were performed. These included assess­

ment of patients' general condition, expression of

pain syndrome, and measurement of tumor dimen­

sions. The toxicity of chemotherapy with reference

to its inffuence on hemopoiesis was also deter­

mined for all groups of patients. The most

expressed signs of the toxic action of chemothera­

py were found in patients in group I who received

combined endolymphatic chemotherapy and radia­

tion therapy. The mean value of the Karnofsky

Index decreased from 71.3 to 66.4. In contrast,

practically no toxic eHects were found in patients in

group II, treated with Ukrain. Moreover, in these

patients an improvement in the general condition

and appetite was observed, as well as the disap-

Patient groups Ukrain therapy

2

10 2 2

24

pearance of partial intestine impassability. Group II

patients displayed a certain improvement in hemo­

poiesis with a statistically significant rise in ery1hro­

cyte and lymphocyte counts, while patients treated

with combined endolymphatic chemotherapy and

radiation therapy showed a tendency to develop

anemia and lymphopenia. The Karnofsky Index

increased to 78.3% from 70.8%. The most pro­

nounced changes in immune status were also

observed in group II patients who received Ukrain

monotherapy (Table II). In this group a substantial

rise in the T- and B-Iymphocyte counts, increased

phagocytic activity of neutrophils, and an increased

content of immunoglobulins A, M, and G were

observed. Reduced plasma concentration of AFP,

CIC and CEA was characteristic for group II

patients. No marked changes in immune status

were detected in group I patients.

Reduced tumor dimensions were found in both

groups of patients after preoperative therapy.

Preoperative X-ray therapy in combination with

endolymphatic 5-FU led to resorption of tumors in

up to 18% of cases, while the mean value of tumor

resorption with Ukrain monotherapy was 22%.

Various kinds 01 rectal resection were performed

following preoperative therapy. The majority of the

surgical interventions (95.2%) were sphincter-sav­

ing in character and involved various kinds of

abdominal-anal resections 01 the rectum. Two 223

224

Bondar G.v. et al.

Table" Some parameters characterizing the immune status and hemopoiesis of patients

Parameters 5·FU + X-ray therapy Ukra in therapy before after before after

Erythrocytes 3.9 ± 0.35 3.4 ± 0.21 3.9 ± 0.36 4.11 ± 0.24 Leukocytes 9.2 ± 0 96 7.4 ± 0 88 9.3 ± 1.21 9.1 ± 1.51 Lymphocytes 23.8 +3.17 17.6±2.17 23.9 ± 4.01 26.6 ± 4.12 Rod-shaped 11.8 ± 2.57 13.8 ± 3.21 12.1 ± 2.56 9.4 ± 8.87 Segmented 55.8 ± 3.7 57.6 ± 2.96 55.3 ± 3.61 53.4 ± 3.58 Eosinophils 3.5 ± 1.11 2.8 ± 0.93 3.2 ± 0.84 4.3 ± 1.24 Monocytes 5.6 ± 1.09 5.9 ± 1.13 6.1 ± 1.13 5 8 ± 108 Proteins 7102 ± 2.16 67.4 ± 1.31 69.2 ± 2.03 76.1 ± 2.67 Bilirubin 18.1 ± 3.12 21.6±3.18 18.6 ± 2.64 16.9 ± 2.21 T-Iymphocytes 38.8 ± 2.86 34.1 ± 2.79 39.3 ± 3.26 46.2 ± 3.48 S-Iymphocytes 9.12 + 1.37 8.4±1.89 9.14 ± 136 11.2 ± 2.71 Neutr. phag. activo 80.2 ± 1.91 85.4 ± 1.51 86.4 ± 2.02 98.1 ± 2.1 CIC 279.2 ± t7.6 296. t :!: 19.31 273.1±18.1 211.6±15.31 AFP 20.7 ± 2.81 30.1 :!: 3.03 26.2 ± 2.01 5.1 ± 0.84 GEA 4.8 ± t02 4.5 ± 0.87 4.8 ± 0.91 1.2 ± 0.16 MGA 16.2±1.83 18.4 ±2.12 17.8 ± 1.93 4.1±0.76 IgA 2.93 :t 0.86 3.14:t 0.56 2.87 ± 1.17 4.12±1.63 IgM 0.76 ± 0.11 0.86 ± 0.18 0.72 ± 0.12 0 96 ± 0.21 IgG 12.6 ± 185 14.2 ± 1.47 12.8 ± 1.42 19.1±2.34

5-FU = 5-flurouraCil; GIC = circulating immune complexes. AFP = (l-tetal protein; CEA = car cio-embryonal antigen; MCA = mucln­cancer antigen.

patients with tumors of the anal canal underwent

resection according to Keny-Mylse . In total, postop­

erative complications developed in nine (18.8%)

cases. Postoperative complications were found to

develop mainly in patients from group 1 - 7 cases

(29.1 %). In contrast, no postoperative purulent

inflammatory complications were revealed in group

II patients. Atony of the urinary bladder developed in

two (8.3%) patients treated with Ukrain monothera­

py.

Clinical observation of all patient groups was

conducted for a period of 14 months. Six months

after the first course of Ukrain monotherapy, all

patients in group II were subjected to repeated

Ukrain treatment with 10 mg i.v. every other day, up

to a cumulative dose of 100 mg. In the course of

observation of group I patients who received com­

plex chemotherapy and X-ray therapy. the continu­

ation of tumor development was observed in eight

cases (33.3%). Relapses of the colarectal tumor

into the small pelvis parenchyma were registered

in five cases (20.8%) and metastases to the liver in

three cases (12.4%). These problematic patients

were subjected to a repeated course of tile com­

plex chemotherapy and X-ray therapy. One patient

(4.1 %) with metastatic liver injury died 11 months

following surgical intervention.

In contrast, prolongation morbi were detected in

only four patients (16.6%) in group II who received

Ukrain monotherapy during pre- and postoperative

periods. Of these, one man had a tumor relapse in

the pararectal parenchyma, and one woman had

multiple metastases to the liver. The man was sub­

jected to an additional two courses of therapy with

Ukrain (100 mg per course) in combination with X­

ray treatment aimed at the site of the relapse. This

succeeded in stabilizing the situation. The woman

received symptomatic hepatotropic therapy. In all

Comparative evaluation of the complex treatment of rectal cancer patients

cases prolongation morbi were revealed in

patients who had metastasis in regional lymphatic

nodes.

Discussion

Ukrain monotherapy considerably improved the

state of oncological patients before surgical inter­

vention, while radiation and chemotherapy caused

immune system suppression and impairment of

some metabolic and homeostatic mechanisms.

These led to a worse prognosis for further treat­

ment. It must be mentioned that pronounced scle­

rosis and heavy bleeding of the minor pelvic tis­

sues during surgical intervention, which normally

occurs after chemo- and radiation therapy, proved

to be practically absent after Ukrain pretreatment.

The latter proved to facilitate considerably surgical

interventions and to bring about fewer intra- and

postoperative complications. Over 2 years obser­

vation, eight group I patients (33.3%) had rectal

cancer relapses and four group II patients (16.6%)

expreienced rectal cancer relapses. This is certain­

ly indicative of the greater eHiciency of the complex

therapy based on Ukrain administration in colorec­

tal cancer patients.

Conclusion

The data obtained in the course of this random­

ized investigation of patients suHering form tumors

located in the ampullar part of the rectum points to

the conclusion that Ukrain monotherapy exerts a

more poweriul anticancer and immune system

stimulating eHect in comparison with traditional,

broadly-used 5-FU chemotherapy in combination

with X-ray treatment. Therefore, we can recom­

mend Ukrain as the most eHective preparation for

adjuvant therapy of colorectal cancer

References

(1) Nichols P.H., el al. Peri-operative modulation of cellular

immunization in patients with colorectal cancer. Exp. Immunol.,

94, 4, 1993.

(2) Punt C. J., et al. Continuous infusion of high-dose 5-fluo­

rouracil in combination with leucorovin and recombinant interfer­

on-a-2b in patients with advanced colorectal cancer. A multicen­

ter Phase 2 study Cancer, 72, 2107, 1993.

(3) Chlopkiewicz B., Marczewska J., Eichart A., Anusewska

E., Koziorowska J. Evaluation of mutagenic, gen% xic and trans­

forming properties of Ukrain. Drugs Exptl. Clin. Res., XVIII

(Suppl). 31, 1992.

(4) Juszkiewicz T., Minla M., Wlodarezyk 8., Biernacki 8.

Teratological evaluation of Ukrain in Hamsters and rats. Drugs

Exptl. Clin. Res., XVIII, 23, 1992.

(S) Kleinrok Z., Jagiello-Wojtowicz E., Matuszek 8.,

CJiodkbwska A. 8asic central pharmacological properties of thio­

phosphoric acid alkoloid derivatives from Chelidonium maius L.

Pol. J. Pharmacol. Pharm., 44, 227 , 1992.

(5) Kleinrok Z, Jagiello-Woi10wicz E., Nowicky J 'II'.

Chodkowska A., Feldo M., Maluszek 8. Some pharmacological

properties 01 prolonged administration of Ukra in in rodents.

Drugs Exptl. Clrn. Res, XVIII (Suppl.), 93, 1992.

(7) Remiszewska M., Wutkiewicz M., Jastrzebski Z.,

Czyzewska-Szatran H . . Danysz A. Pharmacological effects of

Ukra in in rats and rabbits. Acta Pol. Pharm., 49, 43, 1992.

(6) Wyczolkowska J., Czuwai M., Maslinskl C. The

immunomodulating preparalion Ukrain does not induce anaphy­

lactic sensitization in mice and guinea pigs. Drugs Exptl. Clin.

Res., XVIII (Suppl.) , 35,1992 .

(9) Danilos J., Zbroja-Sonlag '11'.. Baran E., Kutylcio L.,

Kondratowitz L., Jusiak L. Preliminary studies on the effect of

Ukrain (Tris (2-(5BA-(S8A,68,12BA)) 58,6.7. 12B, 13, 14 -hexahy­

dro-13-methyl [1,3J benlodioxolo [5,6.Cj IS-dioxolo [4,5,1)

pilenanthridinium-6-olj-ethaneaminylj phosphinesulfide 6HCL)

on the Immunological response in patients with malignant

tumors. Drugs Exptl. Clin. Res , XVIII (Suppl .), 55, 1992.

(10) Liepins A Enhancement 01 cell mediated lysis on tumor

cells by Chelidonium Maius L. alkaloids; (Ukrain). J. Cancer Res

Clin. Oncol. , 116 (Suppl.), 10, 1990.

(11) Nowicky J. '11'., Saniszowski A., Zbroja-Sontag '11'., Siesak

8., Nowicky '11'., Hiesmayr 'II'. Evaluation of IhiopllOsphoric aCid

alkaloid derivatives Irom CheiJdoniurn ma/us L ("Ukrain') as an

immunosrimulanr in patIents with vanous carcinornas. Drugs 225

. -

(

DRUGS EXPTL CUN. RES. XXII(Suppl) 43-50 (1996)

COMPARISO N OF CHEMOTHERAPY AND X-RAY THERAPY WITH UKRAIN

MONOTHERAPY FOR COlORECTAL CANCER

SUSAK Y_M.\ ZEMSKOV V.S.l·, YAREMCHUK O.Y.l, KRAVCHENCO O.B.\ YATSYK I.M.t, KORSH 0.8.2

1 ) Department of General Surgery and Department of Oncology , Ukrainian State Medical University, Gorkogo St. 1 50-15, Kiev, U kraine.

2) Ukrainian Anti-Cancer Institute, Margaretenstrasse 7, 1 040 Vienna, Austria .

Summary: Ninety six colorectal carcinoma patients were included in a randomised study. 48 were trea­ted with Ukra in monotherapy (15 with metastatic and 33 with nonmetastatic colorectal carcinoma) and 48 with 5-fluorouracil (5-FU) and X-ray therapy (the same randomised groups). The results of therapy including clinical, haematological, immunological and biochemical parameters show that Ukra in has favourable properties in the treatment of colon and rectal cancer as a monotherapy because of its mali­gnotoxic and immunomodulating action. Objective response rate in the group of metastatic colorectal cancer treated by Ukrain was 40% There was no registered tumour regression in the group treated by 5-FU Operability is strongly facilitated by pretreatment with Ukrain. The survival rate (up to 21 months) in the Ukrain-treated patients with nonmetastatic colarectal cancer was 18.6% and 33.3% in a corre­sponding control group. Ukrain is a new effective drug in the therapy of colorectal cancer. It can be useful both for the therapy of metastatic colorectal cancer and for neoadjuvanl therapy of nonmetastatic colorectal cancer.

Introduction

Ukraine is chemical ly a Chelidonine th iopho­sphoric acid deriva t ive: Tr is[2-{[5bS-(5ba,6 b, 1 2 b a )J-5 b , 6.7. 1 2 b , 1 3.1 4-h e x a h yd ro-1 3-methy l[l, 3] benzodioxolo[5 , 6 -c-] -l, 3 -d ioxolo[4.5-iJphenanth rid injum-6 -01]-ethaneaminylphosphine­sulfide 6HU (Patent No. 4.970.212. USA, 1 990 ). (Fig 1)

High toxici ty and unsa tisfactory resul ts of 5-fluorouracil require fur ther i nves t igat ion to f ind new agents for colorectal cancer treatment (1 , 2).

. Author to whom correspondence should be addressed

0378-650 1!96JOOOOO�3 + 8 $2 SOlO

Ii ,�------o o

o.

Fig. 1 Formula 01 Ukra In

67

43

44

Susak Y.M. el al.

Table 1 TNM and Dukes' Staging in colon carcinoma

Palienl group Ukrain

TNM-Staging Dukes'

1. Cancer of reClum T,NoMo a T�,Mo a T,NoMo b,

T�,Mo b,

T3NoMa bz T.NoMa b2 T3N,M, hep c T.N,M, c T.N3M, hep c

2. Cancer 01 sigmoid T�Mo a T3NoMo b, T3N,Mo c T.N,Mo c T,N,M, hep c

3. Cancer of ascend- T3NoMo b2 ing colon T3N.M, hep c

T,N)M, hep c T,NJM, hep c pancreas

4. Cancer of caecum T,NoMo b2 T,N,Mo b2 T,N,M, hep c

New properties of Ukrain are broadly shown (3-8) with special immunological activities in vitro, in vivo and clinically (9-13) The malignotoxic pro­perties of Ukrain were evaluated on difierent can­cer cell cultu re lines (E ORTC, Eu ropean Or ganisation of R esearch and Treatment of Cancer, The Netherlands: E90/029, W122, UKRS-222; NSC B238865; National Cancer Institute, Bethesda, Mar yland, USA NSC 631570-W/1) (14. 15). It was shown that Ukr ain increased macrophage tumouricidal activity in murine ade­nocarcinomas (16).

Published results from the National Cancer Institute, Bethesda, Maryland. USA (17) showed that Ukrain (NSC 63 1570) had a more than lOC-

67

Palienl group 5-Fluoroufacil

No. of piS. TNM-Slaging Dukes No. 01 piS.

1 T,NoMo a I

4 T�,Mo a 2 2 T�oMo b, 3 4 T.,N,Mo b, 3 4 T3NoMo b2 3 4 T,NoMo b2 2 4 T,N,Mo c 2 1 T,N,Mo c 1

2 T)N,M, hep c 4 T,N,M, c 1

T.N)M, hep c 2

1 T,NoMo a 1

3 T.,NoMo a 1

2 TJNoMo b, 4

2 T)N,Mo c I

2 T,N,Mo c 2 T,N,M, hep c 1

T.N,M, hep c 1

T)NOMo b2 1 2 T)N.M, hep c I 1 T,N)M, hep 3 c 2 1

2 T .,N.Mo a 1

2 T)NOMO b2 3 2 T,N.Mo b2 2

48 T,N,M, hep c 2 48

fold higher cylotoxic activity on human colon car­cinoma cell culture l ines (Colo 205, OLO-1 , HCC-2998, HCT-116, HT29, KM12, KM20L2, SW 620) than the traditionally broadly-used 5-fluorouracil (NSC 19893). In the EORTC study Ukrain was toxic to the colorectal cell line CXF. It was the aim of this study to show whether there is a correlation of the in vitro effects of Ukrain to clinical experien­ce, and to evaluate the usefulness of Ukrain as a new drug in the treatment of colorectal cancer.

The toxic and immunosuppressive influence of cytostatic agents has adverse effects on homeo­stasis in colon cancer patients. Oncological the­rapy would require maximal toxicity againSI tumour cells and minimal toxicity to Lle organism

268

wi th improvement of the immune system. This is one of the properties of Ukrain (1 8-21 ) .

The aim of this controlled cl inical study was to compare the resul ts of four g roups of patients with colorectal carcinomas treated with Ukrain or 5-FU and to find new therapeutic possibilities for these severe diseases.

Pat ients a nd methods

96 patients (48 mal e ) with colorectal carcino­mas were included in this controlled clin ical study (Table I ) . Their average age was 59.7 years. All tumours were histologically verified as adenocar­cinomas of various degrees of differentiation (sta­ging according to Table I after the Tumour node metastasis (TNM) classification ) . All patients were informed about the therapeutic properties of the preparation and advised that they might stop treatment at any t ime. They gave their wri t ten a g re e m e n t for the t h erapy a f t e r the E t h i c Commission approved the study. The study was performed in accordance with the Declaration of Helsinki ( 196 4 ) , revised in Tokyo (1 975 ) , with sub­sequent Venice ( 1 983 ) and Hong Kong (1 98 9 ) amendments . Randomisat ion was carried out using a computer programme. The study proto­cols were accepted by the Arzneimittelbeirat at the Bundesministerium fUr Gesundheit , Sport und K o n s u me n t e n s c h u t z , A u s t r i a a n d t h e E t h i c Commission o f Kiev Medical University Clinic.

There were four randomised groups: 1 ) metastatic colorectal cancer patients treated

with Ukrain ( 1 5 patients ) ; 2) non-metastatic coloreclal cancer pat ients

treated with Uk-rain (3 3 patients); 3) metastatic colorectal cancer patients treated

with 5-FU ( 1 5 patients ) ( 1 st control group) ; 4 ) non-metastatic colorectal cancer patients

t rea ted with 5 - F U (3 3 pa t ien t s ) (2nd control group).

In the 1 st Ukrain-treated group of 1 5 patients with metastat ic colorectal cancer, pal l iative opera­t i o n was per fo rmed in 1 2 cases . I n t h e 2nd Ukra in - t reated group of 3 3 patients. radical sur­gery was perform2d In 25 cases. pal l ia t ive sur-

Ukra in therapy for colorected cancer

gery in 3 cases and 5 pa t ien ts were t reated without operation. Ukrain-treated groups received 10 injections of 1 0 mg (two ampoules of 5 mg each ) Ukrain every second day, i .v. , total dose: 100 mg. The first course of Ukrain was performed before operation, followed by an interval of 1 0 days, and then the identical course was repea­ted. Neither chemotherapy nor X-ray therapy was periormed before or during treatment with U krain .

I n the 1 st control group of 15 metastatic colo­rect a l cancer pat ien t s , pal l i at ive surgery was periormed in 7 cases; two patients received X-ray therapy. In the 2nd control group of 33 patients, radical surgery was performed in 23 cases, pal­l iat ive surgery in 4 cases and 6 patients were treated without operation . Eleven patients recei­ved X-ray therapy. The control groups received two courses 5-FU 600 mg/m2 every second day. injected Lv. together with salt solution (400 ml ) to a total amount of 5 .5-6.0 g. The first course of 5-FU was before surgery and the second course after surgery. The symptomatic therapy was the same for both groups. The Karnofsky index was between 50 and 90% for all patients.

The therapeutic effect was evaluated by com­parison of the results of the investigations made before and after the therapies. including clinical control and different haematological. immunologi­cal and biochemical parameters. endoscopic and u l t rasound exami n a t i ons, a n d assessment o f common and specific reactions after application of the d rugs.

The following methods were used to evaluate the parameters: lymphocyte subsets were defi­n ed with IKO-3 1 (CO-8 ) for T-suppressors ( 1 6 ) . IK0-86 (CD-4 ) for T-helpers (Moscow Oncological Centre ). The activity of killer cells was determined with 3H-uridine (22 ) . Immunog lobulins A. M and G were found in human sera by radioimmunodiffu­s ion. The phagocyt ic act iv i ty was determined microscopically by eva lua t i ng the phagocyt ic activity of neutrophils on staphylococci. The pha­gocytic index was the average number of bacte­ria lysed by one n e u troph i l ic ce l l . Pat homor­phological studies of tumour b iopsies were car­ried out on pat ien ts before and after t reatment with Ukrain and wi th 5-FU. The survival rate was

2 6 9

6 7

45

4 6

Susak Y.M . e t a/.

measured from the date 01 randomisation to death or to the date of last communication.

The criteria for treatment toxicity were defined by the World Health Organization (23).

Results

G roup 1 pat ients with metastat ic colorectai cancer, who had received Ukrain, showed after 5-6 injections in all cases ( 1 00%) from day 10 to 1 2 improvement of their general condition, decrea­sed toxic signs, decreased fatigue and vomiting , reappearance of appetite, reduced subfebri l i ty and improvement of sleep. Ten patients (66.7%) after t reatment not iced a local e ffect such as decreased rectal bleeding, improvement of laecal movement and decreased local pain. Colostomy was postponed in five patients. After two courses 01 Ukrain treatment, the Karnofsky index increa­sed from 60. 7 to 72.9. Tumour nodes became sof­ter and more movable. Objective decrease in the size of primary tumours or liver metastases in metastatic colorectal cancer after Ukrain t reat­ment was noticed in 6 of 1 5 cases (response rate 40%). Of the four metastatic colorectal carcinoma p atients started on Ukrain therapy in 1 993, three h a d durat ion-ol- l i fe over 1 5 months and one patient is stil l alive after two years.

Group 2 Ukrain-treated patients with colorectal cancer showed in 30 cases (90 .9%) notable improvement of genera l condi t ion; in 13 cases (39.3%) there was a positive local effect , wi th decreased local pain; tenesmus and rectal bleed­ing stopped. Resectability was achieved in eight patients. No metastases were seen during opera­tion . Decrease 01 bleeding from tumour tissue at m echan ic contact a n d absence o f u lcerat ion were noted. After two courses 01 U.krain treatment the Karnofsky index increased from 70.6 to 79. 4 . O f 1 4 patients in the second group treated b y Ukrain i n 1 992- 1 993, 1 1 (78.6%) are still alive; two of them were not operated and nine had radical surgery. Only one patient h as died from Ihose operated radically.

In both Ukrain-trealed g roups. toxici ly was 0 according to WHO cr iteria . No general or loca l

6 7

negative responses (including allergic reactions) to administration of the preparation were repor­ted. Three patients had an increase in body tem­perature up to 38°C during the first three injec­tions but afterwards the temperature returned to normal .

Patients in the 1 st control group with metasta- . tic colorectal cancer showed after 5-FU therapy subjective deterioration in general condition in 14 cases (93 .3%) . We observed worsen ing of the general status, appetite , sleep and appea­rance of fa t ig u e . I n tox ica t ion s igns in these patients increased : nausea ( toxicity 2 ) , lethargy (toxicity 2), cardiac dysrhythmia (toxicity 1 ) , and hand-foot syndrome (according to WHO cr ite­ria) The Karnofsky index decreased from 63.6 to 55.0 after courses of 5-FU therapy. Improvement of the local status (decrease of local pain and cessation of recta l bleeding) was observed in only one case (6.7%) in a patient receiving X-ray therapy. Objective regression of primary tumour or metastases was not observed. From the three patients treated by 5-FU in 1 993, no one l ived more than t 1 mon ths . In 1 2 cases (80%) we observed hepatotoxic or nephrotoxic eHects of 5-FU and in five cases chemotherapy was stop­ped bec au se of an i n c r e a s e of h epatotox i c effects manifested in two to three-fold increases in transaminase activity and an increase in bi l iru­bin level above normal . Nephrotoxic eHects were revealed by the appearance of protein in the ur ine and a r ise of c reatinine by more than 20% .

Patients i n the 2nd control group of colorectal cancer showed a deterioration in their general condition in 29 cases (87.9%). Local eHect was registered in only three cases (9. 1 %) receiving X­ray therapy. The Karnofsky index decreased from 70.3 to 65.6 after 5-FU therapy. Hepato-, riephro­and neurotoxic i ty were observed in 20 cases (60.6%); in three cases there was only one course of 5-FU because of loxicity. Of I he 1 5 patients treated by 5-FU in 1 992- 1 993, after the 21 -months observation period five are st i l l alive (33.3%); in three cases there was radical surgery and in two cases pal l iative surgery. Of 1 0 patients wilh fatal outcome. f ive were operated radically.

The median values of the haemalological , bio·

Table II Median values 01 haemalologica/. Oiochemical and

immunological paramelers

UKRAIN Therapy Conlrol: FU Therapy belore aher be"". aher

e<y1tvocy1,s 100form' 4.01 <022 4 .02.0.24 3.98<0.36 3.31 .0.24

le\.I<ocyIes IO'/tm>' 9.62. 1 .42 9.02. 1.7 9.53rtJ.99 8.66.0.99

IyfrlJ/lOCy1 es 23.00<4.09 29.18.4.15 24.411.2 86 1 7. 1212. 1 1 1Od·s/laped 1223<4.9 9 313.4.6 1 1 .37.2.44 13.87.3.84

�Ie<l 55.35.3.1 53.76.3.6 56.3112.31 58.55.2 89

e<>Wopn;ls 3. 4 1 10 . 7 1 423.0.00 3.� . 1 . 1 1 2.82. 1 .02 monocytes 6.22.1.01 5.431 1 . 1 2 5.00.1.09 6.2 1 . 1 . 16 I.pet. lymph. 1.52<0.29 3.63<024 1 .62.0.21 1.0IhO.20

T-!ymphocy1es 39.8.2.87 45.89.3.45 3926.3.37 34.3 1 . 3.23

�es 8.87. 1.47 10.64.2.98 9.34. 1.03 7.<461 1 . 38

�pet 29.0412.67 3 1 .64. 1 . 65 30.32.2. 1 1 24.061 1 . 1 1

T·supp<essor 30.04 1 1 .45 23.881 1 . 55 30.1212 8 27.43.3.09

HIS (alia 0.97<0.07 1 .32.0. 1 1 1 .01.0.12 0.88<0. "

g<aroIar lymphs '" 1 .49<0. 1 1 3.47.028 1 .67.027 1 .05.0.22 NC-aclivily 25.43.3.33 37.96.4.12 24.9!3.3.02 27.1.4.53 Ohag. aC1ivlly 86.6 1 0 1 .33 99.12.2.05 86.46. 1.84 89.16.2.65 0ha9. ;,de, 9.4 2 . 1 22 14.06. 1 .34 9.87. 1 .30 9.46 . 1.08

SCOT U� 0.29<0 00 021 .0.03 0.33,007 0.92.0.4

SCPT U� 0 35<0.00 0.30.0.04 0.33,0.08 0.56.0.3

19'\ mcglml 2.88 . 1 . 1 2 4.07. 1.02 2.9 1 , 0 82 3.0 1 .0 56 19M mcglml 0.72.0. 1 1 0.85,0. 1 2 0 18.0. 1 1 0.98.0.2' IgG mcglrnl 12.23 . 1 42 18.54.221 1 1 .98" .66 1-4.8-4 1. 1 . 7.

elK ngftTi 2 1 1 . 84 . 1 7.3 202.331 15.82 281.4 1 .202 JOS.43.21.8

InlMefon IU 15.3 . 1 .6 2 1 .8.2.0 15.9.2.6 10.1. 2 3

P'OIeins gldl 75.2 1 . 1.66 14.�.2.05 14.48.3.61 69. 72.2.55 t>lil\..lbrn mgJdl 18.39.322 11.92.2.96 18.61,'.43 22.39.2.88

s.odium m val 1�2.5�S 22 136.6. 1 88 142.3.4.96 133.8.6 42

oocassivm m val 4.15.0.42 4 .2 1 .0.91 •. 17.0 56 3 96.0.16

c.h e m i c al a n d i m mu n o l o g i cal p a ra m eters are shown in Ta ble I I . Positive changes in the Ukrain treated gro u p were recognised in the following parameters : . 1 . Increase in tymphocytes, B-Iymphocytes. 2. Decrease in erythrocyte sedimen tation rate . 3. Tendency to increase of T- Iymphocytes (Fig. 2): increase of T-helpers (Fig. 3) 4 . Increase in killer cell activity (Fig. 4) 5. Increase in phagocytic ac tivity and phagocytic index. 6 Normalizat ion 01 the HIS ratio. 7 . Increase in I g G .

Ukrain therapy for c% rected cancer

belore U atter U botore 5FU dO( 5FU

Rg. 2 Evalualion of T- and B·lymphocy1es.

25 20 1 5 10 5 °

befo<e U aHer U before 5FU aHer 5FU

Fig. 3 Evalualion of T-helper and T-suppressor cells.

8. Decrease in Circul ating immune complexes. 9. Increase in large g ranular lymphocytes (Fig. 5) 1 0 . Inc rease i n p e ri ph e r a l blood lymphocytes (Fig. 6) 1 1 . No negative changes in biOChemical status.

Histological examination of tumour areas from biopsies showed a relative decrease of the ade­nocarcinoma mass, but a n i n c rease of tumour necro s i s . I n va d in g l y m p h o c y t e s we re fou n d . Some cases showed sclerosis o f t h e s troma of adenocarcinoma. Prod uction of mature collagen was seen in the stroma of one case of rectal can­ce r. Necroses appea re d in per ivascular a reas. Prol i fera t i on a n d d e ve l o p m e n t of m e t a s t a s e s during t h e i n tervals between biopsies were not noticed.

The control group with 5 · f luorouracil therapy showed in blood examinations: 1 . Te ndency to d e c re a s e i n e r y t h rocytes a n d Iymphocyles. 2 Decrease in the immunolog ical parameters. 3. tncrease of the circulat ing immune complexes. ". Decrease of the HIS rat io. 5. Tendency to decrease of the large g ranulated

? 7 1

6 7

47

48

Susak Y.M. et al.

40 35 30 25 20 1 5 1 0

5 o

Ag. 4 Evaluation 01 natural killer (Nt<) cytotoxicity.

J I. I • • LJ OOfO<e U aner U 0010<9 SFU anN SFU

Fig. 5 Evaluation of large granular lymphocytes (LGL).

Fig. 6 Evaluation of peripheral blood Iymphocy1es.

lymphocytes . No positive changes in blood parameters and

immunograms were observed in patients from the control groups.

The g roups t reated with Ukrain showed less bleeding during endoscopic procedures than the control g roups. No wounds were seen after bio­psy in Ukrain-treated patienls in contrast to the control g roups .

Discussion

Results of treatment wi ttl 5-FU in our control group do not appear to d dier from results in other c l inical repons. Combination of 5-FU with i n terfe-

fj 7

ron-alpha-2b for treatment of colorectal cancer has not been shown to be more effect ive (2, 24 · 26). No synergis t ic act iv i ty exists between the combination of 5-FU and alpha-interferon (24).

The present control led c l in ica l study shows clearfy the major effects, atoxicity and tolerability of Ukrain in patients with colon carcinomas when compared with the traditional cytostatic therapy with 5-FU. The immunostimulating properties con­nected with the cancerostatic properties of Ukrain a l low an improvement of the general status of advanced colorectal cancer patients whose other pos s ible therapy modal i t ies had a l ready been exhausted. The most important result achieved by treatment with Ukra in was the possibility of chan­g i n g an inoperab le s t a t u s to operab i l i t y and resectability of tumours.

I n respect to parameters of colorectal carcino­ma patients before and after treatment with Ukrain or 5-fluorouracil our studies clearly show advan­tages of therapy with Ukrain , in contrast to 5-FU therapy, for a/l randomised groups. The objective response-rate in the group of metastatic colorectal cancers treated with Ukrain was 40%, while there was no tumour regression in the group treated with 5-FU. We observed improvement of general status. decrease of f a t i g u e , res tora t ion of appet i t e , decrease o f toxic signs ( 1 0- 12 days from stan of treatment) in patients treated with Ukrain in 90.9· 1 00% of cases. In patients of the control groups who received g enerally accepted therapy inclu· ding 5-FU, we observed worsening of the general status, appetite and sleep, together with appearan· ce of fatigue, in 87.9-93.3%. Local improvement was registered in 39.3-66.7% cases under Ukrain therapy and in 6 .7-9. 1 % of 5-FU-treated patients only if they had concomitant X-ray therapy In the group treated with Ukra in we observed disappea­rance of toxic s igns : nausea, le lhargy, cardiac dysrhythmia, with a toxicity of 0 according to WHO criteria. In the control group increased signs were observed: nausea (toxicity 2), lethargy (toxicity 2) . cardiac dysrhythmia (toxicity 1) and hand-loot syn· drome, according to WHO cri teria.

The survival rate up to 21 months in the Ukraln group was 78 .6%; in the corresponding control group it was 33.3% . The survival rate was analy·

sed tram 1 4- 1 5 patients in the 2nd and 4th grou­ps from the years 1 992- 1 993. The remaining 69 patients started their treatment only in 1 994 , so too short a time has elapsed for evaluat ion of the results, which is reasonable only after 1 2 months. For this reason these cases are not incl uded in the survival rate control. Their results will be publi­shed later.

We have no doubt that Ukrain is a necessary component in treatment modal ities of colorectal carcinomas. This study has shown that the high sensibility of human colorectal cancer in the clinic corresponds to the in vitro results of colon cancer cell l ines ( 1 7). These re sults indicate the brood introduction of Ukrain in the treatment of human colorectal cancer. Co nclusion

This s tud y shows the many advantages of Ukrain the rapy, com pared with stan dard thera­pies, in patients with Colorectal cancer. Ukrain reduces the primary tumour and metastases in 40% of metastatic colorectal ca ncer patients and can be useful in these cases. With preoperative a n d p o s t o p e ra t i ve a p p l i c a t ion of U k ra i n , the results of the treatment were improved so that we can recommend Ukrain for neoadjuvant therapy of colorectal canc er.

References

(1) Nichols P. H. el al. Peri-operative modulation of cellular immuniza tion in pa/ienls wilh coloreclal cancer. Clin. Exp. Immunol., 94, 4 , 1993.

(2) Punt C.J. et al. Conlinuous infusion of high �ose 5-fluo­rourac/J in combinatioll with leucovorin and recombinant interie­ron-alpha-2b in p$lienls with advanced c% reetal cancer. A Mullicenler Phase 2 Sludy. Cancer, 72, 2107, 1 993.

(3) Chlopkiewicz B , Marczewska J., Ejchart A, Anusewska E., Koziorowska J, Evaluation of mutagenic, genoloxic and Ir­

ansforming properties of Ukra in. Durgs ExpU. Clin. Res., XVIII (Suppl.), 3 t -34, t 992.

(4) Juszkiewicz T., Minla M .. Wlodarczyk B . . Biernacki B. Teratological evalualion 01 Ukrain in hamslers and rals. Drugs Exptl. Clin. Res., XVI I I (Suppl.). 23-29, 1 992.

( 5 ) K l e i n r o k Z . . Jagie l l o , W oilowicz E . . M a t u s z ek B , Chodkowska A Basic central pharmaological properties 01 Ihiophosphonc acid alkaloid derivatives Irom Chelidonium Majus

Ukra in therapy for colorected cancer

L. Pol. J. Pharmacol. Pharm., 44, 227, 1992. (6) Kteinrok Z., Jag i e l l o-Wojtowicz E . Nowicky J . W . ,

Chod kowska A., Feldo M . , Matuszek B . Some pharmacological

properties of prolonged adminislration of Ukra in in rodents.

Drugs Expll. Clin. Res., XVIII (Suppl.), 93-96, 1 992. (7) Remiszewska M . , Wutkiewicz M . , Jas trzebs ki Z . ,

CzyzeWSka-Szafran H .. Danysz A . Phannacotogica/ effecls of Ukrain in rats and rabblls. Acta Pol. Pha011., 49.43, 1 992.

(8) Wyczolkowska J .• Czuwaj M., Maslinski C. The immuno­modulating preparation Ukrain does not induce anaphylactic sensitization in mice and guinea pigs. Drugs Exptl. Clin. Res., XVIII (Suppl.), 35-38, 1 992.

(9) Danilos J . , Zbroja-Sontag W., Baran E . , Kutylcio L . , Kondratowicz L, Jusiak L. Preliminaty studies on the effect of Ukrain (Tris (2-{5BS-(5BA , 6B, 12BA)J-5B, 6. 7, 12B, 13, 14-hexahydro- 13-methyl( I,31 benzodioxolo(5. 6 · CI- I -3-dioxo-10{4,5,iJphenanthridinium-6-0LJ-ethaneaminyl}phosphinesuI fido· 6HClj on the immunological response in patients with malignant tumours. Drugs ExpU. Clin. Res., XVIII (Suppl.), 55· 62, 1992.

(10) Uepins A. Enhancement of cell mediated lysis on tumor cells by Chelidonium Majus L. alkaloids (Ukrainj. J. Cancer Res. Clin. Oncol., 116 (Suppl.), A3 1 1 8. 1 0, 1 990.

( 1 1 ) Nowicky J.w., Staniszewski A .. Zbroja ·Sontag W . . Siesak B., Nowicky W., Hiesmayr W. Evaluation 01 thiophophoric acid alkaloid derivatives from Chelidonium Majus L. ("Ukrain ") as an immunostimulanl in patienls with various carcinomas. Drugs Exptl. Clin. Res .. XVIII, 139-143. ' 99 1 .

( 12) Slesak 8., Nowicky J.W., Harlozinska A. In vitro effects of Ihiophosphoric acid deriva tives from Chelidonium Majus L on normal lymphocyte subpopulation. J. Cancer Res. Clin. Onco!., 1 1 6 (Suppl.) , A3. 1 1 2 .SO, 1 990.

(13) Siesak B., Nowicky J.w. , Harlozinska A. In vitro effects of Chelidonium Majus L. alkaloid Ihiophosphoric acid conjugates (Ukrainj on Ihe phenotype of normal human lymphocytes. Drugs Exptl. Clin, Res .. XVIII (Suppl.), 17-2 1 , 1992.

( 14 ) Hohenwarter 0., Strutzenberger K., Katinger H .. Liepins A, Nowicky J.w. Seleclive inhibition of in vitro cell growth by the anli-Iumour drug Ukra in. Drugs Exptl. Clin. Res., XVIII (Suppl.), 1 �4 , 1992.

.( 15) Lipiens A., Nowicky W, Ukra in is selectively cytostatic and/or cytotoxic 10 human tumour end HI V-infecfed cells but not to human normal cells. Recent Advances in Chemotherapy, Anticancer Section. Proceedings of the 1 7 t h Int ernational Congress of Chemotherapy, Berlin, 1 99 1 .

( 1 6) Sotomayor E . , R a d K . , L o p e z D . M . , L i e p i n s A . Enhancement 01 macrophage tumouricidal activity by the alka· Ioid derivative Ukrain. In vrtro and in vivo studies. Orugs Expll Clin. Res., XVIII (Suppl.), 5·1 1 , 1 992.

( 1 7) Nowicky J.w . . Nowicky W. , Liepins A. Cytostatic and cytotoxic effects of Ukra in on malignant cells. 8th Mediterranean Congress of Chemotherapy, A t h e n s . Greece, May 1 992. J . Cllemioterapia, 5 (Suppl. 1 ) . 797, 1 993.

( 1 8 ) Liepins A .. Nowicky J.W. Activation 01 spleen cel/ lytlc

2 7 3

6 7

4 9

50

Susak YM .. e/ at.

activity by the alkaloid thiophosphoric acid derivative; Ukrain. Int. J. Immunopharmacol., 14, 1437. 1 992.

(19) Nowicky J.w. New immune-stimulating anti-cancer pre­

paration "Ukrain". 13th International Congress 01 Chemolherapy,

Vienna 1 963. PS 1 2 5 331A-6, part 288157.

(20) Nowicky J.W., Ueplns A. , Staniszewski A., Slezak B., Nowicky w.. Hlesrnayr W. The malignotoxk: and immune modu­lating property of the elkBlokf derivative Ukra in. J. Cancer Res.

Clin. 00c0I., 1 1 8 (SuppI.), VI.09.05, 1992. (2 1 ) Vatanasapt V. et al. Preliminary report on dink:al expe­

rience In the use o( Ukra in. Thai Cancer J., 1 7, 20, 1991. (22) Kampf M. at al. Some problems Involving in virro cellular

cytotoxicity essay. Natl. Cancer Inves!., :rr. 37, 1 973.

6 7

(23) Miller A. el al. Reporting results 01 cancer treatmenl.

Cancer, 47, 207, 1 981 . (24) Pinman K. et al. Pharmacokinelcs 01 5·lIuorouracil in

colorectal cancer patients receiving interferon. Ann. Oneol. . 4. 5 1 5, 1 993.

(25) Tsujimure T. et al. Treatment 01 advanced gastric and

coforedal cancer with 5·FU, leucovorin and interferon, alpha.

Gan.To. Kagaku. Ryoho. 20. 493. 1993. (26) Mitomi T. et al. Rendomized oontrolled study on 8di�vant

immunotherapy with PSK in cumlively resected ooloreetal can·

cer. The Cooperative Study Group of Surgical Adjuvanl Immuno· chemotherapy for Cancer of Colon and Rectum. Gan. To.

Kagaku Ryoho .. 16. 224 1 . 1 989.

2 7 4