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Vol.

7 - I985

Pharmaceutisch Weekblad Scientific Edition

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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.

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Vol. 7 I985 Pharmaceutisch Weekblad Scientific Edition


-

H3N\ / C I
H3N
/
Pt

CI

H3N,\ Pt / \ CI NH3

/C{

0 N~PI \ O H3 1

H2

H2 /N~pt,/ C/

0 .CH2

- -

FIGURE I

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

%0

Schematic structures of cis-diamminedichloroplatinumOI) and trans-diamminedichloroplatinum(lO 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.
Correlations between structure and activity of Pt-compounds

H2 /t'~l H2C

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

~o
%

' 2"-c/I--",
H2 H--C/ C H 3 C4 3''

!/',o

%.

C3

H2 N \Im/OH Cl
lai r

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

cm N/I\ H--C OH Cl
H2 /.
FIGURE 2

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


H 2 H 2 5 H2 H2

Schematic structure of platinum compounds with amine ligands that show antitumour activity

the Pt compounds to the DNA and the binding to the DNA in the cells.
Hydrolysis reactions of cisplatin

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

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

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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]~
FIGURE 3

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

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

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

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

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NH3

Vol. 7 - I985 Pharmaceutisch Weekblad Scientific Edition


.H20~. / NH3 O'" Pt~. H2O~ NH2 /

P,I~

H2N~

~N~

GUANINE

Sugar

ADENINE

Sugar

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.
TRINUCLEOTIDES AND TETRANUCLEOTIDES

.,N% /., ,t.,


"2~ \ 3 H

.,N%,/,, ?,,,
I

CYTIDINE
FIGURE 4

Sugar

ADENINE

Sugar

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

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

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

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 " , ,// NH3 - Pt - G NH.3 '.

monofuncflonolly bound
FIGURE 5

mtersfrond crosslink

introstrand crossh nks

DNA-orotem crosshnk

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.

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

D(.OTt: .

C -

T 3

C ~l

G - G - T - C - T - C"')'z 5

10

f..L~- PT

/\
D( I c, _ CI - g\G'/Gp,f I - C - I - C3'~

PT G6 T - C7 8 T - C~')" 9 10
J

_..._~

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

I - C3 tl

G5
C -

FIGURE 7

- G - A - G -

C - A - G - A - Go,)

D(S'G-

A-

G-

A - C-

C - G - A-

G - A3 ' )

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 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

Vol. 7 - I985 Pharmaceutisch Weekblad Scientific Edition 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

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.

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.

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Pharmaceutisch Weekblad Scientific Edition

179 14 Prestayko AW, Crooke ST, Carter SK,eds. Cisplatin, current status and new developments. New York: Academic Press, I98O. ~5 Rosenberg B. Some biological effects of platinum compounds. Plat Met Rev 197I;I5:42-4. ~6 Reslova S. The induction of lysogenic strains of Escherichia coli by cis-dichlorodiammineplatinum(iQ. Chem Biol Interact I972;4:66-7o. ~7Harder HC, Smith RG, Leroy AF. Template primer inactivation by c/s- and trans-dichlorodiammine platinum for human DNA polymerase ct, [3, and Rauscher Murine Leukemia Virus reverse transcriptase, as a mechanism of cytotoxicity. Cancer Res I976;36: 382I-9. ~" Gellert RW, Bau R. X-ray structural studies of metalnucleoside and metal-nucleotide complexes. In: Sigel H, ed. Metal ions in biological systems. Vol. 8. New York: Marcel Dekker, 1979:I. ~ Brouwer J, VandePutte P, Fichtinger-Schepman AMJ, Reedijk J. Base-pair substitution hotspots in GAG and GCC nucleotide sequences in Escherichia coli K-I2 induced by cis-diamminedichloroplatinumOl). Proc Natl Acad Sci USA I98I;78:7oio- 4. -~) Fichtinger-Schepman AM J, Lohman PHM, Reedijk J. Detection and quantification of adducts formed upon interaction of diamminedichloroplatinum(n) with DNA, by anion-exchange chromatography after enzymatic degradation. Nucl Acid Res I982;IO:5345-56. 2t Fichtinger-Schepman AM J, Van der Veer JL, Den Hartog JHJ, Lohman PHM, Reedijk J. Adducts of the antitumor drug cis-diammit~edichloroplatinum(I 0 with DNA: formation, identification and quantitation. Biochemistry I985;24:707-I3. Rahn RO. Chromatographic analysis of the adducts formed in DNA complexed with c/s-diamminedichloroplatinum 0I). J Inorg Biochem I984;21:3I I-2I. Plooij ACM. Effects of cisplatin and related cis- and transplatinum compounds on cultured mammalian cells: -genotoxic properties and their molecular background. Leiden: State University of Leiden, I984. Dissertation. 24 Chottard JC, Girault JP, Chottard G, Lallemand JY, Mansuy D. Interaction of ctk-[Pt(NH3)2(H20)2](NO3)2 with ribose dinucleoside monophosphates. J Am Chem Soc 198o; 1o2:5565-72. Den Hartog JHJ, Altona C, Chottard JC, et al. Conformational analysis of the adduct cis-Pt(NH3)2d(GpG) in aqueous solution. A high field (500-300 MHz) nuclear magnetic resonance investigation. Nucl Acid Res I982;Io:4715-3o. 26 Den Hartog JHJ. Cisplatin induced distortions in DNA. Leiden: State University of Leiden, 1985. Dissertation. 27 Marcelis ATM, Den Hartog JHJ, Reedijk J. Intrastrand cross-linking of the guanines of the deoxytrinucleotide d(G-C-G) via cis-Pt(NH3)2Cl2. J Am Chem Soc 1982; IO4:2664-5. Marcelis ATM, Canters GW, Reedijk J. Chelation of ct~-Pt(NH3)2CI2 by the deoxynucleotide d(C-C-G-G). Recl Trav Chim Pays-Bas I98I ;Ioo:39I-2. 29 Tran-Dinh S, Neumann JM, Girault JP, Chottard JC, Igolen J, Huynh-Dinh T. Conformation of d(ATGG)cisPt(NH3)2 in aqueous solution by proton magnetic resonance spectroscopy. Inorg Chim Acta 1983;79:2534. ~o Girault JP, Chottard JC, Guittet ER, Lallemand JY,

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. 8 Van Kralingen CG. Antitumor Platinum Compounds: Synthesis, structure and biological activity. Delft: Delft University of Technology, I979. Dissertation. Marcelis ATM. Interaction of antitumor platinum compounds with nucleic acid fragments. Leiden: State University of Leiden, I982. Dissertation. ~c,Marcelis ATM, Reedijk J. Binding of platinum compounds to nucleic acids, in relation to the antitumor activity of cL~-diamminedichloroplatinum (n) and derivatives. Recl Trav Chim Pays Bas I983;Io2:I2I-9. N Martin RB. Hydrolytic equilibria and N7 versus NI binding in purine nucleosides of c/s-diamminedichloroplatinum(H). In: Lippard SJ, ed. Platinum, gold and other metal chemotherapeutic agents: chemistry and biochemistry. Washington American Chemical Society, t983:231-44. (ACS Symposium Series. Vol. 209). 22 Lippard SJ. New chemistry of an old molecule: c/sPt(NH3)2C12. Science I982;218:to75-82. J3 Pinto A, Kippard SJ. Binding of the antitumor drug c/s-diamminedichloroplatinum(n) (cisplatin) to DNA. Biochim Biophys Acta t985;78o:t67-8o.

I80 Huynh-Dinh T, Igolen J. Specific platinum chelation by the guanines of the deoxyhexanucleotide d(T-G-GC-C-A) upon reaction with cis-[Pt(NH3)2(H20)2](N03)2. Biochem Biophys Res Commun I983;IO9: I x57-63. 3t Caradonna JP, Lippard SJ, Gait MJ, Singh M. The antitumor drug cis-[Pt(NHa)2CI2] forms an intrastrand d(GpG) cross-link upon reaction with [d(ApGpGpCpCpT)]2. J Am Chem Soc I982; 1o4: 5793-5. 32 Den Hartog JHJ, Altona C, Van Boom JH, Van der Marel GA, Haastloot CAG, Reedijk J. cis-Diamminedichloroplatinum(u) induced distortion in a doublehelical DNA fragment. J Am Chem Soc i984;IO6:15283~ .

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33 Marzilli LG, Reily MD, Heyl BL, McMurray CT, Wilson WD. Evidence for similar structural changes on binding of platinum anti-tumor agents to DNA and nucleosomes. FEBS Lett I984;I76:389-92. 34 Den Hartog JHJ, Altona C, Van Boom JH, Reedijk J. A phosphorus NMR study of the reaction products of c/s-diamminedichloroplatinum(u) with a double helical oligonucleotide and with DNA. FEBS Lett 1984; I76:393-7.

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

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