Effects of trans-RuCl2(DMSO)4 on B16 melanoma in mice

Pharmacological Research, Vol. 21, Supplement 1,1989

EFFECTS OF

127

~-RuC12(DMSO)4

ON B16 MELANOMA IN MICE

S. Pacor, E. Luxich, V. Ceschia, G. Sava, E. Alessio*, G. Mestroni* Ins ti tute of Pharmacology,

Facul ty of Pharmacy and

( *)

Department of

Chemical Sciences, University of Trieste, 1-34100 Trieste, Italy Key words: Ruthenium complexes - B16 melanoma - anti tumour Ruthenium complexes appear to be the most promising compounds among non-platinum metal coordination complexes studied for cancer chemotherapy. Several studies in non-human systems indicate imidazolium derivatives of ruthenium(III)

and

cis-ruthenium(II)dichlorotetrakisdimethylsulphoxide

(~-RuC12(DMSO)4) endowed

(1-3). More recently, its

~-

with antitumour and antimetastatic properties

~-RuC12(DMSO)4

was shown to be more potent than

isomer in the Lewis lung carcinoma (4). With the present study,

the effects of

~-RuC12(DMSO)4

are investigated in the B16 melanoma

model, by determining the effects on primary tumour, on lung metastases and on the survival time of mice treated with i.p. or i.v. injections. Data

reported

in

Table

I

show

that

dosages

of

reduce ~-RuC12(DMSO)4 and of ~-RuI2(DMSO)4 significantly growth of the primary s ,c , tumour in mice bearing B16 melanoma.

equimolar

The

the

effects on the survival time are less impressive and consist of a 18.3% increase of

the average

life-span

compared

to

untreated

controls. An

Table 1. Effects of ~-RuC12(DMSO)4 and ~-RuI2(DMSO)4 on primary tumour and on the survlva1 time in mice bearing B16 melanoma. Compound

Dose mg/kg/day

Controls ~-RuC12(DMSO)4 ~-RUI2\DMSO)4

100 138

Tumour weight (mg) %1 mean.:tS.E. 2096+467 800+220** 10591257*

62 50

Survival time (days) mean.:tS.E. (min max) 21.9+2.4 25.9+2.1 25.9+2.8

%1: percent inhibition compared to untreated controls; *: p~0.05, **: p
(14-35) (19-37) (19-37)

test. 50 mm 3 of tumor test compounds on 14.

higher prolongation of the survival time of the treated hosts by 30% is achieved when trans-RuC1

is given Lv. at 100 mg/kg/day on days 2(DMSO)4 1,5,9,13 after tumour implantation. At the same time, the Lv. treatment

with

trans-RuC1

significantly reduces the formation of lung 2(DMSO)4 3 metastases in mice bearing i.m. implanted B16 melanoma. The tumour (25 mm 1043--6618/89/2110127-02/$03.00/0

© 1989 The Italian Pharmacological Society

128

PharmacologicalResearch, Vol. 21, Supplement 1, 1989

B16 melanoma fragments),

implanted lorn.

into the calf of the left hind

leg, was surgically removed 14 days later under Ketalar anesthesia (125 mg/kg i.p.) and drug treatment occurred on days 1,5,9,13 post surgery. In these conditions,

~-RuC12(DMSO)4

significantly reduces the number of

lung colonies by 78.6% and their weight by 99.5% (p
computerized

Mann-Whitney U-test). The number of mice without metastases increased from 21% (group of controls)

to 43% (treated group) i

the percentage of mice

wi th metastases weighing more than 1 mg was reduced from 50% of control s to 0%.

The

increase

~-RuC12(DMSO)4

of the

and

for

dai ly

dose

used

for

~-RuI2(DMSO)4

up

i •p, to

treatment 141

and

wi th 195.2

mg/kg/day, respectively, is devoid of severe toxicity (loss of body weight at the end of treatement by 4.38% and 4.32%,

respectively).

increase of tumour inhibition or of prolongation of the

However,

survival

no

time

resulted from this experiment. These data show that

~-RUC12(DMSO)4'

besides its anti metastatic

efficacy already documented on Lewis lung carcinoma anti tumour properties in the

B16 melanoma system.

(4), The

exhibits also

effects

on

this

latter tumour, unlike those on Lewis lung carcinoma, consist of a parallel and marked inhibition of primary

tumoUr. growth and of lung metastatic

dissemination. This finding suggests qualitatively different activities of ~-RuCI2(DMSO) 4'

depending on

the tumour line used and indicates B16

melanoma more susceptible than lewis lung carcinoma to its effects on the primary site of tumour growth.

Acknowledgements: This work was supported by Grants from Italian Ministry of Education (MPI 60%) and from Fondazione C. e D. Callerio. References: 1. Keppler BK, Balzer W, Seifried V. Synthesis and antitumor activity of

triazolium-bis-(triazole)-tetrachlororuthenate(III) and bistriazolium triazolepentachlororuthenate (III). Arzneim-Forsch/Drug Res 1987; 37:770-1 2. Garzon FT, Berger MR, Keppler BK, Schmahl D. Comparative antitumor activity of Ruthenium derivatives with 5'-deoxy-5-fluorouridine in chemically induced colorectal tumors in SO rats. Cancer Chemother Pharmacol 1987; 19:347-9 3. Sava G, Zorzet S, Giraldi T, Mestroni G, Zassinovich G. Antineoplastic activity and toxicity of an organometallic complex of ruthenium(II) in comparison with cis-POD in mice bearing solid malignant neoplasms. Eur J Cancer Clin Oncol 1984; 6:841-7 4. Sava G, Pacor S, Zorzet S, Alessio E, Mestroni G. Antitumor properties of dimethylsulphoxide ruthenium(II) complexes in the Lewis lung carcinoma system. Pharmacol Res 1989; 5:in press