Critical Reviews in Oncology/Hematology 42 (2002) 297– 308

www.elsevier.com/locate/critrevonc

Rhodium and its compounds as potential agents in cancer

treatment
N. Katsaros *, A. Anagnostopoulou
National Centre of Scientific Research ‘Demokritos’, Institute of Physical Chemistry, Agia Paraske6i Attikis 15310, Greece

Accepted 9 October 2001

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

2. Dimeric rhodium(II) compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

3. Rhodium(I) derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301

4. Rhodium(III) derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

5. Radioactive isotopes of rhodium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

Biography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

Abstract

The antitumor activity of the inorganic complex cis-diammine-dichloroplatinum(II) (cisplatin) led to the development of other
types of non-organic cytostatic drugs. Numerous platinum other platinum and non-platinum metal compounds were shown to be
effective against animal model tumors as well as tumors in man. However, the introduction of novel transition metal agents in
clinical treatment is exceptionally slow. So far, Ru(II) and Ru(III) complexes have shown very promising properties while the
Ru(III) compound, [ImH][trans-Cl4(Me2SO)(Im)Ru(III)] (Im = imidazole, NAMI-A), is the first ruthenium compound that
successfully entered phase I clinical trials. Rhodium belongs to the same group as platinum and ruthenium. However, rhodium
compounds, analogues to the corresponding platinum and ruthenium compounds that possess significant antitumor properties,
were found to be less effective as anticancer agents mainly due to their toxic effects. Dimeric m-Acetato dimers of Rh(II) as well
as monomeric square planar Rh(I) and octahedral Rh(III) complexes have shown interesting antitumor properties. © 2002
Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Rhodium compounds; Tumor; Antineoplastic

Abbre6iations: Acac, acetylacetonato; Bzac, 1-phenylbutane-1,3-diketonate; COD, cyclooctadiene; Cp, h5-cyclopentadienide; DAP, 2,6 di-
aminopyridine; DDP, diaminodichloroplatinum(II); DPA, diphenylamine; Dtc, dithiocarbamate; Hisonic, isonicotinic acid; Form, N,N%-di-p-totyl
formamidinate; Im, imidazole; NAMI-A, [ImH][trans-(Me2SO)(Im)Ru(III)]; NBD, norbornadiene; PEI, 2-pyridinalethylimine; PIP, 2-pyridinal-
isopropylimine; PMI, 2-pyridinalmethylimine; Sd, sulfadiazine; Sx, sulfizoxazole; TFA, trifluoroacetate.
* Corresponding author. Tel.: +30-1-6503645; fax: + 30-1-6511766.
E-mail address: katsaros@mail.demokritos.gr (N. Katsaros).

1040-8428/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 1 0 4 0 - 8 4 2 8 ( 0 1 ) 0 0 2 2 2 - 0
298 N. Katsaros, A. Anagnostopoulou / Critical Re6iews in Oncology/Hematology 42 (2002) 297–308
1. Introduction
The earliest reports on the therapeutic use of metals
or metal containing compounds in cancer and leukemia
date back from the sixteenth century. They were forgot-
ten until 1960s when the antitumor activity of the
inorganic complex cis-diamminedichloroplatinum(II)
(cisplatin) was discovered [1]. This led to the develop-
ment of other types of non-organic cytostatic drugs.
Cisplatin has developed into one of the most frequently
used and most effective cytostatic drugs for the treat-
ment of solid carcinomas [2] and particular for testicu-
lar cancer. Cisplatin and carboplatin (cis-diammine-
1,1%-cyclobutane dicarboxylate platinum) (Fig. 1) are
the only widely used metal-containing compounds as
antitumor agents today.
Numerous other metal compounds containing plat-
inum [3– 5], other platinum group metals and even
non-platinum group metals were then shown to be
effective against tumors in man and experimental tu-
mors in animals. These compounds comprise main
group metal compounds of gallium [6– 8], germanium
[9], tin [10,11] and bismuth [12], early transition metal
complexes of titanium [13,14], vanadium [14], niobium
[14], molybdenum [14] and rhenium [14], late transition
metal complexes of ruthenium [15], rhodium [16], irid-
ium [17], platinum and also copper [18] and gold [19]
(Several of these metal compounds are reviewed in this
issue).
Five non-platinum metal compounds potential anti-
tumor agents have so far entered early clinical trials.
Gallium trinitrate and spirogermanium [8,8-diethyl-2-
[3-(N-dimethylamino)-propyl]-2-aza-8-germaspiro[4,5]
decane (Fig. 2) already passed phase II clinical studies
and have shown limited cytostatic activity against cer-
tain human carcinomas and lymphomas [6]. The two
early transition metal complexes budotitane (cis-
[(CH3CH2O)2(bzac)2Ti(IV)], bzac= 1-phenylbutane-
1,3-diketonate (Fig. 3) [20] and titanocene dichloride
(Cl2Cp2Ti, Cp =h5-cyclopentadienide) have just
reached the end of phase I clinical trials and have been
Fig. 1. Molecular structures of (a) cisplatin, and (b) carboplatin.
Fig. 2. Molecular structure of Spirogermanium.
Fig. 3. Molecular structure of Budotitane.
found to have an unusual pattern of organ toxicity in
man [21]. Titanocene dichloride will soon enter phase II
clinical studies. The ruthenium complex [ImH][trans-
Cl4(Me2SO)(Im)Ru(III)] (NAMI-A, Im= Imidazole)
(Fig. 4) entered recently phase I clinical studies.
Despite the success of cisplatin and some closely
related platinum antitumor agents [22–24] the move-
ment for clinical studies of other transition metal anti-
tumor agents has been exceptionally slow. Most
metallopharmaceuticals have emerged from academic
rather than from commercial pharmaceutical laborato-
ries. The broadening of the chemotherapeutic arsenal
depends on understanding the mechanism of action of
existing antitumor agents, with a view towards develop-
ing new modes of attack. Indeed few of the compounds
here may function in a manner analogous to cisplatin,
which appears to bend DNA by cross-linking adjacent
guanines, thereby causing a class of DNA binding
proteins to adhere to the site [22–24]. Since DNA has
often been proposed as the target of many chemothera-
peutic anticancer drugs several studies have been pub-
lished on those that can interact with nucleic acids [25].
Nevertheless, heavy metals are generally toxic binding
to sulfur and nitrogen sites on proteins and thus can
interfere with a number of modes of metabolism. Sev-
eral metals also exhibit action through redox activity
and gallium appears to operate through the displace-
ment of metal ions in iron metabolism or bone. Possible
advantages in using transition metal ions other than
platinum may involve (a) changes in oxidation state, (b)
additional coordination sites, (c) changes in geometry,
(d) alterations in ligand affinity and substitution kinet-
Fig. 4. Molecular structure of NAMI-A.
 N. Katsaros, A. Anagnostopoulou / Critical Re6iews in Oncology/Hematology 42 (2002) 297–308
ics, (e) increasing solubility and (f) photodynamic ap-
proaches to therapy [25– 32].
The most thoroughly studied compounds, as antitu-
mor agents apart from those of platinum are the ruthe-
nium compounds. Although rhodium belongs to the
same group as platinum and ruthenium and complexes
similar to those of platinum and ruthenium exist they
were found to be less effective as antitumor agents
mainly due to their toxic effects. Ru(III) and Ru(II)
compounds with amines [33], N-heterocyclic (such as
imidazole, indazole, terpyridine etc) [34– 45] and alkyl-
sulfoxide ligands [27,46– 48] exhibit antitumor and
mainly antimetastatic activity.
Since metastatic cancer is particularly difficult to
treat, the antimetastatic activity of the ruthenium
dimethyl sulfoxide complexes particularly NAMI-A
represents an important development. Such complexes
could be of particular use in minimizing the growth of
undetected micrometastases following surgery or radio-
therapy [49,50]. NAMI which recently entered phase I
has good water solubility and is active against a broad
range of tumors including Lewis lung carcinoma, B16
melanoma and MCa mammary carcinoma [51– 53].
Mixed-valent, m-carboxylato complexes of the type m-
[(RCO2)4ClRu2] (R =CH3, CH3CH2) [39] are active
against P388 lymphocytic leukemia [38], possibly by
binding to DNA along the lines of the structurally
similar rhodium complexes. The mixed-valent complex
of ruthenium red [(NH3)5Ru(III)ORu(IV)(NH3)4
ORu(III)(NH3)5]6 + [54] has been used as cytological
stain for over a century and its biological properties
have been well reported [55,56] including a remarkable
immunosuppressant activity [57]. Ruthenium red con-
centrates in tumors [58] and inhibits tumor growth.
The discovery that rhodium(II) carboxylates exhibit
carcinostatic activity prompted several investigations
dealing with the chemical properties and biological
effects of these rhodium complexes.Aspects of the
chemistry, the mechanism of action and the anti-neo-
plastic potential of rhodium and its compounds are
presented in this review with particular emphasis on
their effect on various tumor cells.
2. Dimeric rhodium(II) compounds
The dirhodium tetracarboxylate complexes
[(RCOO)4L2Rh2(II)] (where R= Me, Et, Ph or CF3;
L= H2O or other solvent) (Fig. 5) have been shown
antitumor activity against such tumors as human oral
carcinoma, Ehrlich ascites, L1210 and P388 [59– 67] but
toxic effects have prevented their use.
The dirhodium tetraacetate complex [(CH3COO)4
(H2O)2Rh2(II)] is much more inhibitory toward Es-
cherichia coli DNA polymerase I than RNA polymerase
299
Fig. 5. 6-coordinated cage complex of rhodium(II) carboxylates,
[(RCOO)4L2Rh2(II)], R =alkyl group.
[65,66] and exhibits good antitumor activity against the
Ehrlich ascites tumor, sarcoma 180 and P388
lymphocytic leukemia but little activity against L1210
and B16 melanoma [65].
Antitumor activity increases in the series
[(RCOO)4Rh2(II)] (R=alkyl group) with the lipophilic-
ity of the R group and is independent of its reduction
potential [68–70]. Thus, rhodium(II) acetate (R=
CH3), propionate (R= CH3CH2), butyrate (R=
CH3CH2CH2), pentanoate (R= CH3CH2CH2CH2) etc.
showed a considerable variation in their antitumor
activity against Ehrlich ascites tumor cells in mice, with
the pentanoate complex being the most active. The
complexes markedly inhibited DNA synthesis of
Ehrlich ascites tumor cells in vivo. Rhodium(II) pen-
tanoate was the most potent inhibitor followed by the
butyrate complex [69–71]. The butyrate complex in-
hibits DNA synthesis during S phase development but
is most toxic to cycling cells [68]. Also the lengthening
of the carboxylate R chain beyond the pentanoate
reduces the drugs’ therapeutic efficacy. Recently a new
class of rhodium(II) carboxylates (i.e. Rh(II) citrates)
have been synthesized and shown to be promising
compounds for the chemotherapy [70–72]. However,
due to its high water solubility the Rh(II) citrate com-
plex was complexed with hydroxypropyl-b-cyclodextrin
[72] to alter the solubility and significantly increase
both the encapsulation efficiency and duration of re-
lease from polymer microspheres. Also the 1:1 inclusion
compound of Rh(II)-3-chlorocinnamate, [(ClC6H4
CHCHCOO)4Rh2(II)], in b-cyclodextrin was reported.
Taking into consideration the potential antitumor ac-
tivity of the Rh(II) carboxylate complex and its virtual
insolubility in water its inclusion in b-cyclodextrin may
result in its transference to the aqueous phase [73].
With the same reasoning it was prepared and character-
ized the rhodium(II)-3-fluorobenzoate, [(ClC6H4CH
CHCOO)4Rh2(II)] inclusion compound with b-cy-
clodextrin [74].
Recent structural studies suggest that the antitumor
activity of the dirhodium(II) carboxylates may bear
analogy to that of cisplatin by binding to adjacent
guanines on DNA [75–77], however, activity deriving
from protein binding at sulfhydryl sites remains a possi-
bility [78,79], and may be the mode of inhibition of
300 N. Katsaros, A. Anagnostopoulou / Critical Re6iews in Oncology/Hematology 42 (2002) 297–308
DNA synthesis is via the inhibition of enzymes essential
for DNA synthesis such as DNA polymerase A. When
the effect of rhodium(II) acetate, propionate and
methoxyacetate on the activity of 17 enzymes was
evaluated, all enzymes that have sulfhydryl groups in or
near their active site were found to be irreversibly
inhibited [79]. Those enzymes without essential
sulfhydryl groups were not affected. In each case the
rate of inactivation of the enzymes closely paralleled
the observed toxicity and antitumor activity of rhodium
carboxylates; that is rhodium(II) propionate greater
than rhodium(II) acetate greater than rhodium(II)
methoxyacetate. In addition those enzymes that have
been demonstrated to be most sensitive to established
sulfhydryl inhibitors were also most sensitive to rhodiu-
m(II) carboxylate inactivation [79]. The dirhodium
complexes bind to a variety of proteins including serum
albumin and irreversibly inhibit proteins with cysteines
in the active site [80]. Up to seven molecules of
[(CH3COO)4Rh2(II)] bind to histidyl imidazoles on hu-
man serum albumin affecting both its conformation
and binding sites of other molecules [81,82].
In mammals the butyrate complex requires a plasma
concentration of 0.8 mM to be effective; however the
half-life for the drug is 1 h [68,69]. Maintaining the
concentration at 0.8 mM for 6 h results in host’s toxicity
[69,83]. Injected glutathione decreased the toxicity of
[(RCOO)4Rh2(II)] (where R=C2H5) and enhanced its
antitumor activity against P388 ascites tumors [84].
Complexes of the type [(Form)(CF3COO)2(H2O)2Rh2
(II)] (Form=N,N%-di-p-tolyl formamidinate) (Fig. 6)
showed little activity against the Yoshida ascites sar-
coma and the T8 sarcoma of Guerin on rats [85].
Rhodium(II) trifluoro acetate (TFARh), rhodium(II)
trifluoro acetate adduct with sulfadiazine (TFARh.Sd)
showed increased survival rate on mice bearing Ehrlich
ascite tumors while rhodium(II) acetate adduct with
sulfisoxazole (RhSx) did not exhibit significant activity
[86]. More recently complexes of the type
[L2(CH3COO)2Rh2(II)]2 + (where L= 2,2%-bipyridine or
1,10 phenanthroline) have also shown some antitumor
activity [87]. Also dimeric rhodium(II) cationic com-
plexes of the type [(RCOO)2L2 (H2O)2Rh2(II)]2 +
Fig. 6. Molecular structure of [(Form)(CF3COO)2(H2O)2Rh2(II)].
(RCOO)22 − (where R= CH3, CH3CHOH, C6H5CHOH,
L= 1,10 phenanthroline or 4,7-diphenyl-1,10 phenan-
throline) were synthesized and characterized. Cytostatic
activity of these complexes against the synchronously
cultivated green alga Chlorella 6ulgaris has been investi-
gated. The obtained results indicate that the cationic
complexes [(RCOO)2L2(H2O)2Rh2(II)]2 + show higher
cytostatic activity than the neutral [(CH3COO)4(H2O)
2Rh2(II)] [87,88].
Two new rhodium carboxylate sugar derivatives,
rhodium(II) keto-gluconate (C6H10O7) and glucuronate
(C6H9O7) (and their respective cyclophosphamid ad-
ducts have been described and were found to be active
in vitro against K-562 cells [89]. Treatment of animals
bearing Ehrlich tumor with a rhodium amidate com-
plex [(CF3CONH)4Rh2(II)] showed a 90% survival rate
of the tumor-bearing population [90,91]. The LD50
value for [(CF3CONH)4Rh2(II)] was of the same order
as that of cisplatin and it was verified that the rhodium
complex usually needs lower doses than cisplatin to
promote the same inhibitory effects. Rhodium(II) car-
boxylate (acetate, propionate and butyrate) adducts
with isonicotinic acid (Hisonic), (OCOCR)4(Hisonic)2
Rh2(II)] [where R= CH3, CH2CH2CH3, CH2CH2CH2
CH3, Hisonic = isonicotinic acid= pyridine-4-car-
boxylic acid (C6H5NO2)] were prepared and studied.
The in vitro (K 562 human leukemic cell line) assay and
LD10 in mice resulted that in presence of blood lipids
or cellular membrane, the adducts dissociate into the
parent compounds and the rhodium(II) carboxylate
enters the cell to carry out its biological effects [92].
The crystal structure of the potential antitumor drug
complex [(CH3COO)4(1-methyladenosine)2Rh2(II)]
monohydrate has been determined [93]. The antitumor
effects on Ehrlich ascitic tumor and P 388 leukemia of
the neutral complexes of the type [(CH3COO)4Ln
Rh2(II)] where L=antimalarial drugs plasmaquine, pri-
maquine, pentaquine, amodiaquine, isopentaquine,
mepacrine and chloroquine (Fig. 7) and n = 1 or 2 were
examined. The most promising complex appeared to be
[(CH3COO)4(mepacrine)2Rh2(II)] [94]. The adduct be-
tween rhodium propionate and metronidazole was
characterized by single X-ray diffraction. Rhodium pro-
pionate and its adduct exhibit similar toxicity and
ability to inhibit DNA synthesis. However, the metron-
idazole adduct is more active than rhodium propionate
or metronidazole alone against S. aureus and P. aerugi-
nosa [95].
A range of Rh(II) carboxylates and cis-Pt(II) com-
plexes have been examined for their ability to increase
the radiation sensitivity of aerobic and hypoxic V79
cells in vitro. The transition metal complexes sensitized
in both air and nitrogen, with the greater effect gener-
ally occurring in nitrogen. When compared with the
cis-Pt(II) complexes only showed small levels of sensi-
 N. Katsaros, A. Anagnostopoulou / Critical Re6iews in Oncology/Hematology 42 (2002) 297–308
Fig. 7. Antimalarial drugs (L) in [(CH3COO)4Ln Rh2(II)], (a) primaquine, (b) plasmoquine, (c) amodiaquin, (d) mepacrine, (e) chloroquine and (f)
pentaquine.
tization with dose modification factors (DMFs) of no
more than 1.2, in contrast Rh(II) complexes gave
DMFs of 2.0. Radiation chemical experiments showed
the transition metal complexes to have substantially
lower redox potentials than metronidazole and, in addi-
tion, neither type of complexes underwent electron
transfer reaction or adduct formation on interaction
with radicals derived from DNA bases. Thus, the inor-
ganic complexes did not operate by mechanisms similar
to those occurring with electron affinity or stable free
radical sensitizers.
The increase in radiation sensitivity for cells treated
with the Rh(II) carboxylates, but not the cis-Pt(II)
complex was attributed to the ability of the Rh com-
pounds to deplete intracellular thiols. Further, the effi-
ciency of sensitization by the Rh(II) complexes and
their ability to interact with cellular thiols depended
upon the nature of the carboxylate ligand and followed
the order butyrate greater than propionate greater than
acetate greater than methoxyacetate. The differences
between the carboxylates may be due to differences in
drug uptake. A combination of the Rh(II) complexes
with misonidazole given to hypoxic cells irradiated in
301
vitro gave an additive response. However, it was not
demonstrated a similar effect in tumors in mice given
the combination of Rh(II) methoxyacetate and the mis-
onidazole analogue RSU 1070 [96].
3. Rhodium(I) derivatives
Antitumor rhodium(I) compounds with in vivo activ-
ity were the organometallic neutral and square planar
rhodium(I) cyclooctadiene complexes [Cl(COD)
NH3Rh(I)] and [Cl(COD)-piperidineRh(I)] (COD=cis-
1,5 cyclooctadiene) which had antitumor activity
against the Ehrlich ascites tumor [97]. Also the acety-
lacetonato (acac) derivative [(acac)(COD)Rh(I)]
[107,108] inhibited the growth of leukemia L1210,
sarcoma 180, and Ehrlich ascites carcinoma and had
antimetastatic activity in the metastasizing Lewis
lung carcinoma. The effect of square-planar
[Rh(acac)(COD)] has been examined in comparison
with cis-dichlorodiammine platinum(II) (cis-DDP). The
complex inhibits the growth of subcutaneous Lewis
lung carcinoma and the development of spontaneous as
302 N. Katsaros, A. Anagnostopoulou / Critical Re6iews in Oncology/Hematology 42 (2002) 297–308
well as artificial metastases. The antitumor activity of
[Rh(acac)(COD)] appears to be of the same magnitude
as that of cis-DDP and it was found to be only
marginally toxic [106– 108].
The square-planar rhodium(I) complexes
[(COD)(PMI)Rh]Cl (where COD=cyclooctadiene and
PMI = 2-pyridinalmethylimine), [(COD)(PEI)Rh]Cl
(where PEI= 2-pyridinalethylimine), and [(COD)(PIP)
Rh]Cl (where PIP=2-pyridinalisopropylimine) exhibit
activity against MCa mammary carcinoma, Lewis lung
carcinoma and lung metastatic tumors [98]. Thus, the
examination of the activity of these compounds on the
lung metastatic tumors indicates that their antineoplas-
tic properties are not simply related to their cytotoxic
action for tumor cells localized in the lungs but it
appears most likely that modifications occurring at the
primary tumor level are responsible for the reduction of
spontaneous lung metastasis formation observed in
treated animals [99]. The examination of the different
effects on primary tumor growth and on the formation
of spontaneous pulmonary metastases in mice bearing
Lewis lung carcinoma, indicated that the former com-
plex having qualitatively the higher solubility in
aqueous solutions and the higher resistance to inactiva-
tion via oxidation displayed the more pronounced anti-
neoplastic activity [105].
Rhodium(I) complexes belonging to the general
structure [Rh(CO)2L] (where L= sulfonamide deriva-
tives) were assayed as cytostatic and antitumor agents
against KB cells in vivo against P388, Ehrlich ascites
and advanced B16 melanoma. The compound
[Rh(CO)2(sulfamethoxydiazine)] appeared to be active
in all biological systems, without showing evident
nephrotoxicity [104]. Organometallic compounds of the
type [Rh(CO)2L] (where L =dithiocarbamate and xan-
thate derivatives) were synthesized and assayed as cyto-
static and antitumor agents in vitro against KB cells
and in vivo against several tumor cell lines P388
leukemia, Ehrlich ascites carcinoma, Sarcoma 180
ascite and ADJ/PC6A solid tumor [100]. Among the
new compounds the Rh(CO)2(DPA-dtc) (where dtc=
dithiocarbamate and DPA=diphenylamine) appeared
to be active in all biological systems without showing
evident nephrotoxic activity [100].
Rhodium complexes adsorbed on polymers, as a way
to improve their transport and solubility properties
were studied as antitumor agents. The complex
[Rh(NBD)(2,4N)]ClO4 (where NBD=norbornadiene,
2,4N =3,3%-dimethylene-2,2%-di-1,8 naphthyridine) was
investigated on primary solid tumors and ascitic tu-
mors, while the complex [Rh(NBD)(3,4N)]ClO4 (where
3,4N = 3,3%-trimethylene-2,2%-di-1,8naphthyridine) was
investigated on ascitic tumors. Poly(oxyethylene) was
used to solubilize these poorly water-soluble com-
pounds and to stabilize them in solution before injec-
tion. These Rh(I) complexes appear to be promising
drugs because of their solubility in aqueous polymer,
their low toxicity as was determined in vivo using
female mice and similarity to cisplatin as they reduce
tumor growth and increase the survival life span of
mice [101].
The neutral organometallic complexes of the types
[Rh(I)(NBD)L] (where NBD = norbornadiene and L=
xanthate anions) were prepared and reported to have
activity on Ehrlich and Landschutz ascitic tumors and
structure activity relations were studied [102,103]. Also
the cationic organometallic complexes of the general
formula [Rh2(COD)2L2]+ where COD =1,3-cycloocta-
diene, L= classical antiparasitic drug, 2-hydroxystil-
bamidine and X= Cl−, ClO4 − , NO3 − , [B(C6H5)4]−,
and also [Rh(I)(COD)L2]+X− where COD =1,3 cy-
clooctadiene, L= classical antiparasitic drugs, ben-
znidazole, nifurtimox, niridazole (Fig. 8) and X=Cl−,
ClO4 − , NO3 − , [B(C6H5)4]−, and the anion of ethylfu-
maric acid, were studied on mice bearing Ehrlich
ascitic, Landschutz ascitic, S-180 and P-388 leukemic
tumors. The most active complex was
[Rh(I)(COD)L2]+[B(C6H5)4]− where L=benznidazole
[106–108]. Although many Rh(I) compounds are not
air stable, all complexes reported in this review are
stable in the air at room temperature.
4. Rhodium(III) derivatives
In malignant cells the amino groups of cellular
proteins are alkylated by homocysteine thiolactone,
forming homocysteinyl peptide bonds. In normal cells
the sulfur atom of homocysteine thiolactone is con-
verted to homocysteic acid, phosphoadenosine, phos-
phosulfate and sulfate ester. N-substituted derivatives
Fig. 8. Antiparasitic drugs (L) in [Rh(I)(COD)L2]+X−, (a) benznida-
zole, (b) nifurtimox, and (c) niridazole (COD = 1,3 cyclooctadiene
and X=Cl−, ClO4 − , NO3 − , [B(C6H5)4]−).
 N. Katsaros, A. Anagnostopoulou / Critical Re6iews in Oncology/Hematology 42 (2002) 297–308
of homocysteine thiolactone synthesized from arachi-
donic acid, pyridoxal and maleimide were previously
found to have antineoplastic activity. One of these
N-substituted derivatives the oxalyl homocysteine thio-
lactone is forming a complex with rhodium trichloride
which also possesses antineoplastic activity in mice with
transplanted rhabdomyosarcoma [109].
An in vivo model of liver hyperplastic noduligenesis
was induced in rats by long-term administration of
thioacetamide (TAM) (50 mg/kg per day i.p.). The
biochemical parameters related to liver function indi-
cated that the disease induced by this substance could
be considered a chronic obstructive biliary disease with
indices of cell proliferation and tumors. When the
Rh(III) complex, [L4Cl2Rh(III)]Cl (L= sulpha-quinox-
aline) was administrated to TAM-treated rats signifi-
cant restoration of the biochemical parameters related
to liver function was observed. The mechanisms, which
this complex acts to counteract the TAM-induced
changes, are not established yet [110,111].
A number of rhodium(III) analogues of rutheniu-
m(III) antitumor complexes also show antineoplastic
activity. Ru(III) complexes which are thought to be
activated by reduction to Ru(II), however Rh(III) com-
plexes is unlikely to be activated by reduction and this
may account for their generally lower activity. Like
fac-[Cl3(NH3)3Ru], mer-[Cl3(NH3)3Rh] is also active but
insoluble in water [112]. While mer, cis-
[Cl3(Me2SO)2LRh(III)](L = NH3 or imidazole) exhibit
significant activity against some tumor cell lines, mer,
cis-[Cl3(Me2SO)(Im)2Rh], Na[trans-[Cl4(Me2SO)(Im)
Rh(III)] and (Him)trans-[Cl4(Im)2Rh(III)] were essen-
tially inactive [113]. Na[trans-[Cl4(Me2SO)(Im)Rh(III)]
and mer, cis-[Cl3(Me2SO)2(Me2SO)Rh(III)] modestly
inhibited the growth of the primary MCa mammary
tumor implanted in mice and the latter compound may
also inhibit metastases of this tumor in the lung
[113,114].
The coordination compound of rhodium(III) with 2,6
diaminopyridine (DAP) exhibited significant effects on
the humoral immune response of white mice [115]. The
nephrotoxic effect of this potential antineoplastic agent
RhCl3(2,6 diaminopyridine) was found to be identical
to cis-dichlorodiamine platinum and PdCl2(2,6 di-
aminopyridine) on sodium and calcium retention in the
whole kidney [117]. The cationic complexes of rhodiu-
m(III) with the antimalarial drugs of the type
[L4Cl2Rh(III)]+Cl− where L= primaquine, mepacrine,
amodiaquine, lepidine, plasmoquine, pentaquine,
isopentaquine were studied for their antitumor effects
on Ehrlich ascitic tumor and P388 leukemia. The most
promising complex was [(lepidine)4Cl2Rh(III)]+Cl−
[116].
Also the photochemistry and the photobiology of
rhodium(III) polypyridyl complexes and psoralen were
studied as potential antitumor agents [118]. Some
303
rhodium metallointercalators exhibit such remarkably
specific DNA binding as to suggest new types of DNA-
targeting agents. The sterically bulky DNA intercalator
D-[(chrysi)(bpy)2Rh(III)]3 + (where chrysi= 5,6 chry-
senequinone diimine and bpy= 2,2%-bipyridyl) [119]
binds specifically to destabilized regions near base pair
mismatches and recognizes a single mismatch in a 2725
base pair plasmid DNA. Such sterically demanding
intercalators may have application in mismatch specific
chemotherapeutic agents or in detecting mutations
[120], thus opening another avenue for transition metal
anticancer drugs.
5. Radioactive isotopes of rhodium
The radiotherapy of choroidal melanoma was intro-
duced in 1974 at Wills Eye Hospital and Hahnemann
University where the cobalt-60 plaques technique was
introduced earlier. During the following years, other
radioactive isotopes were introduced including iridium-
192, iodine-125, ruthenium-106/rhodium-106 and more
recently palladium-103. Patients treated with Ru-106/
Rh-106 brachytherapy for posterior uveal melanoma
showed that although a high proportion of treated eyes
eventually lost a great deal of vision and although
many treated eyes underwent secondary enucleation, a
substantial number of patients treated by plaque radio-
therapy survives well over 10 years and retains the
tumor containing eye with visual ability. Brachytherapy
with 106-Ru/106-Rh plaques can be recommended for
small (T1a,b) and medium sized (T2) choroidal
melanomas with good results [121–123].
Also further studies indicate that enucleation for
choroidal melanoma, especially for cases of eyes with
good vision, may longer be the standard treatment of
these diseases. This appears to be particularly true in as
much as 50% of the patients with large choroidal
melanomas who have enucleation die from metastases
within 5 years of the operation. Therefore conservative
methods such as b-irradiation (106-Ru/106-Rh) can be
used with more or less success to destroy tumor and
save a functioning eye [124–128]. In this respect
fluoresceine or indocyanine-green angiography may
provide valuable information in the follow-up of
choroidal melanoma after 106-Ru/106-Rh plaque ther-
apy especially of the different stages of tumor regres-
sion after local brachytherapy [129,130]. To minimize
radiogenic side effects the duration of irradiation rec-
ommended hitherto 7–14 days should be adhered to
when treating malignant melanomas of the choroid
with beta-ray applicators [131].
Radiation effects on the optic nerve were observed
after brachytherapy of choroidal melanomas with 106-
Ru/106-Rh plaques. The probability of developing
complete radiation optic neuropathy (RON) was 23
304 N. Katsaros, A. Anagnostopoulou / Critical Re6iews in Oncology/Hematology 42 (2002) 297–308
and 53% at 5 and 10 years, respectively. The probability
of developing partial RON was 66% at 5 years and 82%
at 10 years. The probability retaining visual acuity
better than 0.5 was 38% at 5 years and 26% at 10 years
[132]. In 1985, a new form of a beta-ray applicator
106-Ru/106-Rh was described with which it is possible
to treat ciliary body tumors while preserving the
cornea. Radiotherapy with this applicator could be
regarded as an alternative to local excision and radia-
tion of ciliary body melanomas with protons and he-
lium ions [133]. The suitability of a 105Rh-bleomycin
complex was described for potential targeted radiother-
apy. The stability of this complex in plasma is sufficient
to allow targeted delivery of the radioisotope and its
suitability appears to be limited by the renal clearance
of this agent [134].
6. Conclusions
A variety of rhodium compounds have been tested
against various types of tumors. Many of them were
found to express antitumor activities against such tu-
mors as Ehrich ascites, P 388 lympocytic leukemia, oral
carcinoma, L1210 and B16 melanoma, MCa mammary
carcinoma, Lewis lung carcinoma, lung metastatic tu-
mors etc, but none of them is at present under clinical
trial. Although a number of rhodium compounds
showed no evident nephrotoxic activity the toxic effects
of most of the compounds studied prevented further
examination. Their mechanism of action has not been
studied systematically yet. Recent structural studies
suggest that the antitumor activity of a promising class
of rhodium compounds the dirhodium(II) carboxylates
may bear analogy to that of cisplatin by binding to
adjacent guanines on DNA. However the mode of
inhibition of DNA synthesis via the inhibition of en-
zymes essential for DNA synthesis remains a possibil-
ity. The encapsulation of rhodium compounds in
b-cyclodextrins and polymeric materials although it
increases the solubility does not increase overall their
antitumor activity. Brachytherapy with 106-Ru/106-Rh
plaques can be recommended for small (T1a,b) and
medium sized (T2) choroidal melanomas.
Reviewers
Prof. Bernard Desoize, Université de Reims, IFR53/
EA3306, Faculté de Pharmacie, 51, rue Cognacq-Jay,
F –51100 Reims, France.
Prof. Mauro Coluccia, MD, PhD, Department of
Biomedical Sciences and Human Oncology, University
of Bari Medical School, Piazza G. Cesare 11, I–70124
Bari, Italy.
Prof. Dr Bernhard Keppler, University of Vienna,
Institute of Inorganic Chemistry, Waehringerstrasse 42,
A–1090 Vienna, Austria.
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Biography
Nikos Katsaros is Director of Research at the Insti-
tute of Physical Chemistry at the National Center of
Scientific Research ‘Demokritos’ in Athens Greece. He
is head of the laboratory of Bioinorganic Chemistry
and Director of graduate studies at the same Institute.
He is also lecturing in graduate programme of Bioinor-
ganic Chemistry coordinated by the Chemistry Depart-
ment of the University of Ioannina. He is the author of
308 N. Katsaros, A. Anagnostopoulou / Critical Re6iews in Oncology/Hematology 42 (2002) 297–308

more than one hundred scientific papers. He served as member of the COST Chemistry Technical Committee.
Secretary of Science and Technology in the Ministry of He is an assistant editor of the European Journal of
Development. He is a member of the Management Inorganic Chemistry. He also served four times as
Committee of COSTD8 ‘Metals in Medicine’ and a president of the Greek Chemical Society.