Vol.

7 - I985

Pharmaceutisch Weekblad Scientific Edition

I73

review articles

Cisplatin: synthesis, antitumour activity and mechanism of action

J. REEDIJK* AND P . H . M . LOHMAN**

Introduction
The c o m p o u n d PtCI2(NH3)~, has been known for
more than a century and occurs in two isomers, i.e.
trans-PtCl2(NH3)2 and cis-PtCl2(NH3)2. The full
name of the latter isomer is cis-diamminedichloroplatinum(n), abbreviated in the literature as e.g.
cis-DDP, cisplatin, cis-platinum, C D D P , D D P , CP
and P D D . The cis-Pt(NH3)2 moiety is usually abbreviated as cis-Pt in formulae, l The two compounds
have the Pt(n) in a square-planar co-ordination and
do not isomerize under ambient conditions. In
Figure ~ schematic structures are given of these two
platinum co-ordination compounds.
Experiments in the early sixties in which the
growth of Escherichia coli was studied as a function
of the electric field - generated between platinum
electrodes with aqueous NH4CI as the electrolyte showed an unexpected filamentous growth, which
was initially not understood. 2 Subsequent experiments by the same investigators showed that the
origin of the filamentous growth had nothing to do
with the electric field, but was in fact caused by the
presence of small amounts of platinum co-ordination
compounds formed upon dissolution of the Pt
electrodes in the NH4Ci containing solutions)
A m o n g those cis-PtCl2(NH3)2 turned out to be the
most effective in further bacterial tests, and ~ase of
this compound in the treatment of Sarcoma 180
tumours induced in mice, showed that complete
remission was possible in many casesJ
The first clinical trials were reported in I972 with
very promising results. 5 Large scale applications of
the drug had to wait some time, since toxic side
effects, such as vomiting, bone marrow and kidney
toxicity were very seriousJ 6 After improvements in

the administration procedure - based on combination therapy and advanced protocols - the drug
has developed as the leading anti cancer drug in the
USA (30 ooo patients each year) and is also registered widely in E u r o p e and in Japan (there only since
I984).
Interest in the study of the mechanism of action
began about a decade ago. It is generally accepted
that a better knowledge of the mechanism may lead
to better administration procedures and to derivatives or analogues with superior properties. A better
understanding of the mechanism may also lead to a
better understanding of m e t a l - D N A interactions, a
process of great importance in many biological
events. 7

Synthesis of platinum compounds

Upon consideration of the chemistry of platinum,
it is seen that both Pt(n) and Pt(IV) occur frequently.
The Pt(II) compounds usually have a square-planar
geometry, whereas the Pt(w) compounds are octahedrally co-ordinated. Contrary to many other metal
compounds, the platinum compounds exhibit very
slow ligand-exchange reactions. In fact, this slow
ligand-exchange process is the origin that the cis- and
trans-isomers of cisplatin (Fig. i) are not interconverted in solution.
It has also been known for a long time that certain
ligand-exchange reactions on Pt occur relatively
faster than others. These relative reaction velocities
can even be predicted from the so-called 'trans
effect'. According to this rule, ligands in positions
opposite (trans) to a certain ligand in a Pt(n)
compound, are more or less rapidly exchanged

Reedijk J, Lohman PHM. Cisplatin: synthesis, antitumour activity and

mechanism of action. Pharm Weekbl [Sci] x985;7:t73-8o.

Abstract
A review is presented on the successful antitumour drug

cis-diamminedichloroplatinum(n), better known as cisplatin. Special

*Department of Chemistry,
Gorlaeus Laboratories, State
University of Leiden, P.O. Box
95o2, 2300 RA Leiden, The
Netherlands.
**Medical Biological Laboratory
TNO, P.O. Box 45, 2280 AA
Rijswijk, The Netherlands.

attention is given to the synthesis of the compound and related derivatives,

and to the nature of the hydrolysis products in blood and in the cell. In
the second part of the review the mechanism of action is discussed.
Binding to DNA and in particular the formation of intrastrand cross-links
between adjacent guanines, to which the Pt(NH3)2> ion is chelated at the
N7 atoms, seems to be a very important event. However, at the moment
it is not yet known which DNA lesion is responsible for the killing of the
tumour cells.

i74

Vol. 7 I985 Pharmaceutisch Weekblad Scientific Edition

-

H3N\ / C I
/

H3N

Pt

CI

/C{

H3N,\
Pt
/ \
CI
NH3

0
N~PI \ O
H3 1

- -

FIGURE I

Schematic structures of cis-diamminedichloroplatinumOI) and trans-diamminedichloroplatinum(lO

H2
/t'~l
H2C

H2

H2
/N~pt,/

- ~ C ~ C/ CH2 H2C~N/ ~0
C~ H2
3 H2
0
H

0
.CH2
C/

%0

H
H~
__c__ H
C--N\ /O--C~c~
~C ~

~o

!/',o

compared to others. This has resulted in sequences

of reactivity. For instance ligands trans to the
following compounds in the sequence CN->fosfine>NO2->Br->CI->NH3>H20 are most easily
replaced. This means that the ligands in the Pt
compounds in fact determine the reactivity. In
addition to this trans effect rule, one should know
that Pt-amine ligand bonds [such as in Pt(NH3)22 or
Pt(I,2-diaminoethane) 2 are usually very stable,
whereas Pt-H20 bonds and Pt-CI bonds are rather
labile)
With these basic principles one can synthesize all
kinds of c&- and trans-Pt compounds, and one can
understand the reactions of the Pt compounds that
occur in vivo.

Schematic structure of platinum compounds with amine

ligands that show antitumour activity

Correlations between structure and activity of

Pt-compounds

the Pt compounds to the DNA and the binding to the

DNA in the cells.

Apart f r o m t h e above mentioned classical compound cisplatin, nowadays many other compounds
of related structure are known to possess similar
biological activities, and some of these are undergoing intense clinical trials in several countries.
Based on research in this field during the last decade,
it has become evident that - in order to have
antitumour activity - the Pt compounds should at
least fulfil the following structural requirements:
- the geometry of the amine ligands should be cis;
thus: (amine)2PtX2 or (amine)2Pt'"Y2X2;
- the X ligands should be easily leaving groups, such
as Cl-, SO42-, oxalate(2-), malonate(2-), citrate(2-), ascorbate(2-). [N.B. In the case of Pt(iv)
compounds the Y ligands are trans to each other,
and so far only Y=OH- has resulted in active
compounds];
- the amine ligands, or at least one of them, should
have a hydrogen bond donor function, i.e. should
be a primary or a secondary amine.
The compounds depicted in Figure 2 all fulfil these
requirements. This, of course, does not automatically indicate that all these compounds can be used to
cure turnouts. The molecular basis of the side
reactions in blood, organs and tumour tissue are far
from understood and elucidation will need many
years of research by pharmacologists, toxicologists,
biologists and (bio)chemists. Now, only the reactions with DNA are understood to some extent.gThe
remainder of this review will focus upon the route of

' 2"-c/I--",
H2

C3

H--C/
CH3

H2
N\Im/OHCl
lai r

cm N/I\
H--C
OH Cl
C4
3''
H2
/.

%.

H2 H2 H2 H2
/C--C\ / C
N /OH2
P1
H2C
C

\c_c / \c---N / \osm

H2 H2
5

H2 H2

FIGURE 2

Hydrolysis reactions of cisplatin

After administration of the drug - usually through

injection or infusion in the blood stream - a variety
of chemical reactions may occur. Due to the fact that
the chloride ion concentration in blood is rather
high, hydrolysis reactions are relatively unimportant. m~ Such an hydrolysis process is required to
allow fast reactions, with e.g. proteins, RNA,
DNA.~2-~4 Consequently the high Cl- concentration
in blood significantly hampers the binding of cisplatin to blood t~roteins. Nevertheless, significant
losses of Pt do occur, since 50-70% of the administered Pt is excreted within 24 hours, s ~4
The t;emaining cisplatin eventually diffuses
through the walls of (all kinds of) cells, and now because of the much lower Cl- concentration inside
the cells-hydrolysis reactions will take place. Based
on work of Martin u it is now generally accepted that
the hydrolysis scheme as depicted in Figure 3
operates inside the cells. Among the hydrolysis
products, cis-[Pt(NH3)2(H20)CI] + is the predominant species undergoing reactions with all kinds of
molecules present inside the cells (DNA, RNA,
proteins). These reactions are discussed below.
D N A as the most likely target

Early studies by several groups have shown that a

Vol. 7 - 1985 Pharmaceutisch Weekblad Scientific Edition

I75

H20
H20
cis-PtCl2(NH3) 2 ~
cis-[PtCl(H20) (NH3)2]+ ~
[Pt(NH3)2(H20)2] 2+
t~-H+
cIs-[PtCI(OH)(NH3) 2]

H20
~I-H+ PKa.5"6
~
[Pt(OH) (H20)(NH3)2]~

I~-H+PKa=7.3
[Pt(OH)2(NH3)2]
specific interaction of cisplatin with DNA is an
important event, which may eventually lead to cell
killing. The evidence can be summarized as follows:
- induction of filamentous growth indicates that cell
division is hampered and cell growth is not; ~~
- induction of lysis in lysogenic bacteria also indicates interaction with DNA. Even a correlation
between antitumour activity and prophage induction in lysogenic bacteria was found; ~6
- i n h i b i t i o n of DNA synthesis is selectively inhibited, whereas RNA and protein synthesis are
not. ~7
It should be stressed here, however, that although
binding to the DNA is evident, these observations do
not necessarily prove that this binding is the only
important reaction that leads to the cell killing, and
in particular to the killing of the tumour cell.
Nevertheless, detailed binding studies of cisplatin
(and analogues) to DNA and to fragments of DNA,
are receiving considerable attention. The next section will deal with the molecular basis of these
Pt-DNA interactions.
B i n d i n g o f cis-Pt to D N A , D N A f r a g m e n t s and
nucleotides

Although DNA has many components with lone

pairs of electrons where metal ions may bind (i.e. the
phosphate groups, the sugar oxygen atoms, and the
heterocyclic nucleobases), early studies have made
clear that cisplatin preferentially binds at the nitrogen atoms of the nucleobases. ~12 ~8All bases (some
examples are presented in Fig. 4) do have such
nitrogens and have been found to be able to
co-ordinate transition-metal ions. TM However, binding at thymidine can only occur after deprotonation
at N 3, which is not the case under physiological
conditions.
To understand better the binding of cisplatin to
DNA, investigations have started with studies of the
binding preferences of the nucleobases adenine (A),
guanine (G) and cytidine (C). It appeared that
adenine might co-ordinate to the cis-Pt group
through the N7 atom and through the Nx atom,
whereas cytidine can co-ordinate through the N 3
atom. In guanine binding is possible at N7 a n d - only
under alkaline conditions- also at deprotonated Nl.
Of all these binding modes, those at the N7 atoms of
adenine and guanine seem most likely in DNA, since
the other sites of A, G and C are involved in the

FIGURE 3

Hydrolysis reaction equilibria of

ct~-PtCI2(NH3)2. Under physiological
conditions Pt(OH)(H20)(NH~)2 is
the most frequently occurring
species

so-called Watson-Crick base pairing of the double

helix, and are less accessible for the cis-Pt unit. st2 ~8
Detailed kinetic studies and competition studies of
about a decade ago have made clear that guanine N 7
has a strong kinetic preference, and subsequent
investigations have shown that the so-formed
Pt-N7(guanine ) bond is a very stable one. This has
led to the generally accepted view that also in DNA,
cis-Pt units bind to - certain - guanine N7 sites.
However, the cis-Pt unit has two reactive sites (the
NH3 ligands are not reactive enough under physiological conditions) and after binding to one guanine
N7, a second reaction has to be expected.
The site where the second binding occurs cannot
be predicted with certainty, and at this stage only the
several possibilities are briefly mentioned, i.e. :
I. stabilization of the monofunctional binding
through hydrogen bolading of the amine ligands
and/or the remaining H20 or Cl;
2. chelation to an 0 6 group of the same guanine.
This possibility has so far not been proved and is
likely to play no role, at least not for Pt binding to
DNA;
3- chelation to a base in the opposite strand of
double-helical DNA, which may be a guanine or
another base (interstrand cross-linking);
4.- chelation to a (next) neighbouring guanine N 7 in
the same DNA strand (intrastrand crosslinking);
5. chelation to another guanine at the same DNA
strand (not a next neigbour);
6. chelation to another base next to guanine in the
same strand; likely candidates are adenine (N7 or
Nx) and cytidine (N3);
7. chelation to a protein side chain residue.
Investigations from our laboratories - in part
described below - have shown that with DNA from
several sources, both in vivo and in vitro, all but the
second binding mode can occur; they are schematically depicted in Figure 5 .t~23
In vitro studies with salmon sperm DNA by
Fichtinger et al. have shown that the most predominant lesion is the intrastrand chelation with two
neighbouring guanines (a so-called GG chelate).
However, also AG chelation has been found in
significant amounts. -'~ Binding to CG, GC, GA, TG
or GT units could not be demonstrated (T =
thymidine).
For a better understanding of the binding modes 3,
4, 5 and 6 (vide supra) several in vitro experiments
have been performed on oligonucleotides by a

Vol. 7 - I985 Pharmaceutisch Weekblad Scientific Edition

I76
NH3

.H20~. / NH3
O'"
Pt~.

H2N~

~N~

Sugar

.,N% /., ,t.,

\

CYTIDINE

NH2

GUANINE

"2~

H2O~

P,I~

ADENINE

Sugar

TRINUCLEOTIDES

.,N%,/,, ?,,,
H

Sugar

ADENINE

to be of great importance in larger fragments and in

DNA, where more rigid structures occur in double
helices. With GpG rapid formation of a very stable
adduct with both guanine N 7 atoms chelated to cis-Pt
is observed. 2526Detailed N M R studies have revealed
the most likely solution structure of this cis-Pt(GpG)
adduct. One projection of such a structure is redrawn in Figure 6.

Sugar

FIGURE 4

Binding possibilities of cis-[Pt(NH3)2(H20)]2. to guanine

N7, adenine N[, adenine N7 and cytidine N3. The
hydrogen bonding in the guanine adducts (dashed line)
may be of importance for the specific interaction with
guanine
variety of investigators. A brief summary of this
work is presented here.
DINUCLEOTIDES

Starting with dinucleotides of general formula

NpG and GpN (N standing for any base, i..e. G, A or
C, and P representing the phosphate group bridging
between the sugar rings of the nucleotides) it was
found by Chottard and others that in all cases
chelation with the cis-Pt unit does occur. 24-'5 However, in all cases the primary attack of the platinum
species is at the guanine N 7. The secondary binding
mode appeared to be cytidine N 3, adenine N7 and
adenine NI. In many cases more than one geometrical isomer was found, 24 but this is not believed

AND

TETRANUCLEOTIDES

On the trinucleotide level, the binding of cisPt(amine)2(anion)2 to GpGpG, GpCpG, GpTpG

and GpApG are under study or have recently been
published. 27 It appeared that in the case of GpCpG
and GpTpG only cis-Pt adducts are formed in which
both guanine bases chelate via their N 7 atoms to the
cis-Pt unit, thereby proving the possible binding
mode 5 (vide supra). When using GpApG, on the
other hand, also binding takes place at the central
adenine unit, and the final products are 20% cisPt[GpApG-N7(E),N7(3) ] and 80% cis-Pt[GpApGN7(1),N7(3) ]. In the case of GpGpG, the major
product is a chelate with neighbouring guanines
bound to cis-Pt (Van der Veer JL, et al., unpublished
observations).
On the tetranucleotide level, binding of cis-Pt
has been studied with double stranded NpNpGpG
(N = C, A, T) with CpGpCpG (and also with
GpCpGpC).
LARGER

OLIGONUCLEOTIDES

As one would expect, the double helix is disrupted

after Pt binding, and the binding takes place to the
guanine N7 atoms. "~:9 Hexanucleotides containing a
- G p G - unit have been studied by Chottard and
Lippard30 3~and also in these cases the double helices
appeared to be disrupted after chelation of cis-Pt to
the GpG units (again through NT).
Moving to somewhat larger oligonucleotides, the
base stacking and Watson-Crick base pairing be-

cj_ss-Pt (NH3)2 (:12 odducts in ONA

j?\
IG\ / N H 3 ~
X~ / Pf " , ,//

monofuncflonolly bound

mtersfrond crosslink

introstrand crossh nks

NH3 - Pt - G
NH.3

'.

DNA-orotem crosshnk

FIGURE 5

Schematic representations of several possibilities of monofunctional and bifunctional binding of the cis-Pt unit to
DNA

Vol. 7 - I985 Pharmaceutisch Weekblad Scientific Edition

I77

,~
FIGURE

Projections of the structure of the

adduct c/s-Pt(NH3):[d(GpG)] as
deduced from high-frequency NMR
analysis

come quite strong and one could think about possibilities of cis-Pt binding without (complete) disruption of base pairs. Very recently we have shown that
the decanucleotide d(TCTCGGTCTC) and the
complementary strand d ( G A G A C C G A G A ) can
form a double helix after Pt chelation to the central
GpG part of the first strand. 3' [N.B. For clarity the
bridging phosphates have been omitted from the
formulae.] Chottard et al. (Chottard JC, personal
communication) have made similar observations for
deca- and octa-oligonucleotides (see also Fig. 7).
The fact that the double helix remains intact after
cis-Pt binding is rather unexpected and this raises the
question whether or not such a lesion occurs in DNA
in vivo. Very recent work by Marzilli and Den
Hartog, however, has shown that one of the 31p
NMR signals of DNA containing cis-Pt is essentially
similar to that of our decanucleotide dimer (discussed above) after Pt binding. 3334Detailed analyses
of the several possible distortions of DNA after Pt
binding, primarily based on the observed spectral
features, have shown that a kink in the DNA with an
angle of about 40-7 ~ can explain all the observations
available up to now. z6 Future work will deal with
larger DNA fragments and a comparison will be
made of the binding processes and structures of the
formed adducts with those present in DNA of
normal cells and tumour cells (Den Hartog JHJ, et
al., unpublished observations). The first results of
this work are already mentioned below.

D(.OTt: .

C -

T -

C -

G - G - T - C - T - C"')'z

~l

Reactions of cisplatin in the (tumour) cell

DNA

LESIONS

When bacterial cells and cultured mammalian

cells are treated with cisplatin (or derivatives)
considerable binding to its DNA is observed. -'3 In
vitro treatment of DNA yields products of which the
various binding modes are depicted in Figure 5Shortly after treatment of the cells, the monofunctional adduct (mode l, vide supra) can be expected
to be the main product. From these monofunctional
products the bifunctional adducts are formed in
secondary reactions; the .possible products have
been presented also in 9
5- Recent work has
shown that such adducts are also formed after
treatment of human cells with cisplatin. -'3
At this stage it is interesting to note that the trans
isomer of cisplatin (Fig. I) also binds strongly to the
~ellular DNA, both monofunctionally and bifunctionally. However, because of steric reasons no
intrastrand chelates can be formed with the trans
isomer, unless the DNA structure is completely
disrupted. It is tempting to speculate that the
absence of antitumour activity of trans-Pt compounds may be associated with the fact that these
intrastrand cross-links cannot be formed. Whether
this hypothesis is valid is not known yet.
An interesting observation is the fact that in
bacterial cells treated with cisplatin, chelation with
two guanines in the same strand and separated by

10

f..L~- PT
PT

/\
D( I c,

_ C-

I - g-

\G'/Gp,f

D(S'G-

A-

G-

A - C-

I - C - I - C3'~

C - G - A-

G - A3 ' )

_..._~

~ ( )~' T - C 1
2
D(x,A
J

I - C3
tl

- G - A - G -

G5

G6

T - C7
8

T - C~')"
9
10

C -

C - A - G - A - Go,)
J

FIGURE 7

Double-stranded decanucleotides
after binding of cisplatin to the
central GG part of one strand. It
appears that the double-helical
structure can remain intact after
the Pt binding

I78

Vol. 7 - I985 Pharmaceutisch Weekblad Scientific Edition

another base (the GXG crosslink in Fig. 5), appears

to be a promutagenic lesion. Thus, the GXG
chelates seem to be a 'key' lesion that can be
associated with the induction of mutations in bacteria. 19
DELAYED

REPAIR

Binding of the cis-Pt unit to specific DNA bases,

however, does not seem to be the only origin of the
toxic, mutagenic, or cytostatic properties of the
cisplatin drug. All cells are known to possess efficient
DNA repair systems, which allow the cell to remove
most of the DNA damage inflicted by chemicals that
react with the genome (genotoxic chemicals). So also
when cells are treated with trans- or cis-PtCl2(NH)3)2
(or derivatives) the majority of the DNA adducts will
be removed by repair processes. Not all lesions,
however, are repaired with equal efficiency; most
likely the various repair systems in a cell can
discriminate between the different types of Pt-DNA
lesions. In mammalian cells, monofunctional DNA
lesions are quickly repaired,i.e, within a repair period
of 24 h after cisplatin treatment more than 75 % of the
original monofunctional lesions are removed; this
observation holds for both the cis and the trans
isomers. ~3
The repair of bifunctional DNA adducts (Fig. 5) in
mammalian cells seems to be slower than that of
monofunctional ones. It should be realized that
measurement of the repair of bifunctional lesions is
complicated b.y the fact that delayed formation may
occur from - primary - monofunctional DNA
lesions. In model experiments with mammalian cells
in culture, however, it was found that both intrastrand and interstrand cross-links in cisplatin treated
cells are rather persistent. Up to 24 h after treatment
these lesions were still present (Fichtinger-Schepman AM J, et al., unpublished observations; ref. 23).
Interstrand cross-links induced by trans-PtCl2(NH3)2
in mammalian cells are removed much faster'than
those induced by cisplatin.
At this moment it is not yet clear whether delayed
removal of any of the identified bifunctional lesions
can be related to the toxic, mutagenic or cytostatic
properties of cisplatin. Similar observations were
made when DNA-protein cross-links (Fig. 5) were
studied. 23 Again the bifunctional lesions induced by
cisplatin showed a much more persistent character
than those induced by the trans isomer.
Not all- types of cells possess the same repair
capacities for Pt lesions. For example the human
repair-deficient cell lines xeroderma pigmentosum
and ataxia are much more sensitive to treatment by
cisplatin than are normal repair proficient cells.
Until now, it is unknown whether repair deficiencies
are also responsible for the variety in response of
different tumours towards platinum antitumour
drugs. The same holds for the unpredictable results
of Pt treatment of patients apparently suffering from
the same type of tumour.

Preliminary observations by Poirier on the frequency of DNA lesions in peripheral blood lymphocytes, have shown that patients who did not respond
to the cisplatin treatment, indeed had a much smaller
number of Pt-DNA lesions (Poirier M, personal
communication to Lohman PHM, I984). This observation might be of great importance for the understanding why certain Pt compounds show such a vast
difference in activity towards various types of cancer.
No difference in either the Pt uptake or the loss of
DNA-bound adducts, however, could be established
after treatment by cisplatin of sensitive and resistant
rat carcinoma cells (Roberts J J, personal communication to Lohman PHM, I984). Possibly, in contrast
to the resistant cells, the sensitive cells are incapable
of repairing the important, but minor, Pt-DNA
lesion (the 'key DNA lesion').
FURTHER

RESEARCH

For further elucidation of the role of 'key DNA

lesions', of specific DNA repair processes, and of
cellular penetration in the cytostatic action of Pt
compounds, it will be of great importance to continue and intensify the observations on cancer cells
obtained from cisplatin treated patients. The recent
development of extremely sensitive immunochemical methods for the detection of specific adducts in
cells, in vivo exposed to Pt compounds, will allow
such an evaluation (Fichtinger-Schepman AM J, et
al., unpublished observations). These techniques
can even be applied at the single cell level, which
means that only a limited amount of human material
is required for the investigations. Apart from the
great values of these methods for mechanistic
studies, they may also provide a fast and sensitive
tool for the detection of the individual sensitivity of
patients towards - certain - Pt compounds.

Closing

remarks

In this review we have shown that cisplatin (and

derivatives) is a fascinating molecule of great biomedical importance. Combined efforts of biochemists, biologists, chemists, pharmacologists and
toxicologists are beginning to shed some light on the
molecutfir basis of its reactions in vivo. Much further
work will be needed in the coming decade to further
elucidate the several reactions and processes that do
occur in the blood, the organs and the tumour tissue
of cancer patients. Special attention in the next
couple of years will be given to:
further mechanistic studies on derivatives of cisplatin;
detailed studies on the side reactions that do occur
in blood;
detailed studies of the structures of oligonucleotides after binding of cisplatin and derivatives;
- further developments of immunochemical techniques to detect and quantify specific Pt-adducts at
the cellular level.

Vol. 7 - I985

Pharmaceutisch Weekblad Scientific Edition

Acknowledgements
The authors are indebted to their students, coworkers, and colleagues for their invaluable contributions to the research described in this review
paper. Their n a m e s are m e n t i o n e d as co-authors in
the references. Support to the research came from
the State University of Leiden, Medical Biological
L a b o r a t o r y T N O Rijswijk, The Netherlands Organisation for the A d v a n c e m e n t of Pure Research
( Z W O ) , the Netherlands Foundation for Chemical Research (SON; grant I I-28-17), the Dutch
National Cancer Foundation ( K W F ; granted projects M B L 79-I, M B L 83-I, I K W - 8 3 - I 6 ) , Johnson
and Matthey Ltd. (Pt loan), Ciba-Geigy (gift of
K2PtC14). The progress in this research was stimulated through m a n y discussions with Prof. J.C.
Chottard (Paris) and his group, made possible by the
support of the Dutch-French Cultural A g r e e m e n t .
References

Reedijk J. Nomenclature for platinum antitumour compounds. In: Hacker MP, Douple EB, Krakoff M, eds.
Platinum coordination complexes in cancer chemotherapy. Boston: M. Nijhoff, I984:3-8.
2 Rosenberg B, Van Camp L, Krigas T. Inhibition of cell
division in Escherichia coli by electrolysis products from
a platinum electrode. Nature 1965;2o5:698-9.
3 Rosenberg B, Van Camp L, Grimley EB, Thomson AJ.
The inhibition of growth or cell division in Escherichia
coli by different ionic species of platinum(w) complexes.
J Biol Chem I967;242:I347-52.
4 Rosenberg B, Van Camp L, Trosko JE, Mansour VH.
Platinum compounds: a new class of potent antitumour
agents. Nature I969;222:385-6.
~ Roberts J J, Thomson AJ. The mechanism of action of
antitumour platinum compounds. Progr Nucleic Acid
Res Mol Biol I979;22:71-133.
6 Wiltshaw E. Cisplatin in the treatment of cancer. Plat
Met Rev I979;23:9o-8.
7 Marzilli LG, Eichorn GL. Metal-ions in genetic information transfer. New York: Elsevier/North Holland,
I984.
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Vol. 7 - I985

Pharmaceutisch Weekblad Scientific Edition

33 Marzilli LG, Reily MD, Heyl BL, McMurray CT,

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Received N o v e m b e r I984.
Accepted for publication April I985.