Cisplatin enters cells by diffusion, where it is converted to its active form.

This is due to the

lower intracellular chloride concentration which promotes ligand exchange of chloride for water,
and thus formation of the active aquated complex. The actual active species has not yet been
determined with great certainty. However, the most common structure is considered to be the
diaquated form, cis-diaquadiammineplatinum(II).

The principle function of cisplatin is to bind to DNA. The consequence of this, is the activation
of repair processes which eventually cause cell death. This explains why cisplatin is sometimes
classed as an alkylating agent.

Although cisplatin is also able to interact with many types of proteins that are vital to DNA
replication and cell division, its primary target remains to be DNA. Evidence supporting this is
as follows:

1. Observed filamentous growth in bacteria. This effect is almost certainly due to the
selective inhibition of DNA synthesis since cell growth (i.e., RNA and protein synthesis) remains
unaffected whereas cell division does not occur.

2. Mutagenesis. DDP has been shown to be mutagenic in both bacterial (prokaryotic) and
human (eukaryotic) cells. The cis isomer is more mutagenic than the trans isomer, implying
differences in their DNA binding. Further, repair-deficient mutants are more sensitive than those
proficient in repair.

3. Inhibition of DNA synthesis. Compared to its effect in RNA and protein synthesis,
cisplatin consistently and uniquely inhibits DNA synthesis both in vitro and in vivo.

4. Selective binding to DNA. Assessment of platinum binding to macromolecules from

cultured cells at known levels of cell killing and adjustment for molecular weight differences
showed that more platinum was bound to DNA.

Initially, it was reported that O6-Guanine (atom six of guanine), was the site of importance,
being linked with both carcinogenesis and the mechanism of antitumour action.

However, a year later, this proposal was amended . Tests involving the action of cisplatin on a
guanine-like structure (1,3,9-trimethylxanthine), showed it to bind at N7 and not O6. Further
studies revealed cisplatin to preferrentially bind at N7 of the purines adenine and guanine, and at
N3 of the pyrimidines cytosine and uracil.

One research group, examined the steric effects between a closely related cisplatin compound
-triammineplatinum(II), and twelve possible binding sites present in a DNA strand. A "steric-
probe" was used to calculate the lowest Vander Waals repulsive energy between the nucleobase
and platinum complex, Their findings showed N7-Guanine to be the most favoured site. This is
now a generally accepted fact.

Being bifunctional in nature, cisplatin has the ability to bind to two nucleophilic sites.
Considering the previous observations and discussions, it can be concluded that cisplatin will
prefer to bind to two N7-Gunaine sites.

The kinetics of such a process has been shown not to be a simple two-step process. The reaction
of cisplatin with GMP (Guanosine 5'-Monophosphate) was studied with a 500MHz NMR
machine (1H & 31P). The data suggested a series of complex elementary steps, which are shown
below.

If the active species is a monoaquated complex. The recorded values of the rate constants were k'
(=ka + k1[GMP]) = 3.1x10-4s-1, k2 = 2.5x10-2dm3mol-1s-1, and k3 = 1.5x10-4s-1, for 1.0x10-
3M cisplatin + 0.02M GMP at pH6.5. This shows that formation of the monoadduct is the fastest
step.

Cisplatin does not bind just to N7-Guanine sites. It is able to bind to a large combination of
bases, but to within certain restrictions.

To form a biadduct, the two bases must not be more than one base apart. This type of biadduct is
referred to as an intrastrand cross-link.

With the existence of DNA as a duplex, the binding of a base from each strand is possible, but
only to those that are either directly opposite or diagonal to one another., this is referred to as an
interstrand cross-link.

Studies in vitro, using gel mobility shifts, x-ray crystallography and other spectroscopic
techniques, have shown cisplatin to react with DNA to form about

90% 1,2-intrastrand cross-links -- 65% are to two adjacent N7-Guanine sites [5'-d(GG)], and
about 25% are to adjacent N7-Guanine and N7-Adenine sites [5'-d(AG)].

The remaining are other intrastrand cross-links, interstrand cross-links, monofunctional adducts
and protein-DNA cross-links.
 The high occurance of the intrastrand cross-link d(G*pG*) (platinum bound to two adjacent N7-
Guanine sites), has been presumed to be due to minimal distortion and destabilisation, as they
posses the shortest distance between two N7 atoms in DNA. ¤

A widely accepted fact is that the formation of cross-links, is the cause of the drug's cytotoxicity.
However, does the type of cross-link matter?

it has been shown that intrastrand cross-links are the major contributors. A classic example
which shows this clearly is the comparative activity between cisplatin and transplatin.

Cisplatin has long been shown to be significantly more cytotoxic than transplatin, forming
predominantly intrastrand cross-links while transplatin predominantly interstrand. Cisplatin, not
only forms a lot of intrastrand cross-links, it also forms them much more quickly than
interstrand cross-links. However, transplatin has been reported to be "kinetically more reactive
than the cis isomer", and generally more kinetically labile, having a shorter half life than
cisplatin. This has been used to explain its inactivity towards cancer, where the interstrand
cross-links formed are "easier" to repair than intrastrand cross-links. (Dr. S. James, 1998)

Having identified d(G*pG*) (platinum bound to N7 of two guanine residues), intrastrand cross-
links to be the most predominant and cytotoxic, the next step is to find out how and why.

Many studies have concentrated on this area of research and all have made a common
observation - the alteration of the physical structure of DNA when cisplatin is bound to it.

X-ray crystal structure of d(G*pG*) intrastrand cross-links and other spectroscopic

techniques could reveal the direct effects of cisplatin on DNA structure.

The formation of d(G*pG*) adducts caused significant disruptions in base stacking to

accomodate the coordination requirements of the square planar platinum(II) atom. The metal
atom itself was displaced from the planes of the guanine bases by about 0.1nm and was
considerably strained. Distortion of the double helix was severe, causing a degree of unwinding
and significant bending of about 40° away from the site of attachment. ‡

The bound DNA strand was seen to affect the conformation of its complimentary strand in the
form of a kink and a head to head anti-d(G*pG*) arrangement. The disruptions of the duplex
structure were spread over several base pairs, however, the overall structure of the double helix
remained intact. Most of the distortion was absorbed by conformational changes in the sugar-
phosphate backbone near the platinum lesion.
[3D cDDP-DNA]

How does this physical alteration of DNA structrue cause cell death? Cisplatin kills cells at any
phase in the cell cycle, and is said to be phase-nonspecific, although there is now much evidence
that it may be most effective in G1 of the cell cycle.

It is generally believed that the alterations of the DNA structure prevents replication and thus
activation of cellular repair mechanisms which are said to be the cause of eventual cell death.

The link between structure alteration and eventual cell death is prevention of DNA transcription.
There are three mechanisms of action:

1. Participation of HMG-box proteins. These High Mobility Group proteins have a great
affinity for cisplatin-modified DNA, as much as 100 times than that for unmodified DNA. The
reason is due to the resemblence of the bent DNA duplex as a binding site for these proteins.
HMG-box proteins increase cisplatin cytotoxicity by binding onto DNA adducts and obstructing
cellular excision repair.

2. Irreversible platinum binding to transcription factors. Cisplatin is able to replace zinc(II)

of a regulatory protein which is vital for the transcription of DNA .

3. Abortive correction repair. This can occur in many ways, however, it typically involves
single or double stranded breaks caused by DNA polymerase and post-replicative repair
mechanisms. DNA polymerase causes strand breaks by a physical process, whereby it literally
collides with a platinum adduct. Post-replicative repair mechanisms produce nicks and breaks by
mistaking the cisplatin adduct as a mismatched base pair. These strand breaks cause the
apoptosis.
Tertiary and Quarternary structure of DNA

The structure of DNA does not only exist as secondary structures such as double helices, but it
can fold up on itself to form tertiary structures by supercoiling. Supercoiling allows for the
compact packing of circular DNA. Circular DNA still exists as a double helix, but is considered
a closed molecule because it is connected in a circular form.

A superhelix is formed when the double helix is further coiled around an axis and crosses itself.
Supercoiling not only allows for a compact form of DNA, but the extent of coiling also affects
the DNA’s interactions with other molecules by determining the ability of the double helix to
unwind.

Supercoiling changes the shape of DNA. The benefit of a supercoiled DNA molecule is its
compactibility. In comparison to a relaxed DNA molecule of the same length, a supercoiled
DNA is more compact. How this is reflected in experimentation is that supercoiled DNA moves
faster than relaxed DNA. Therefore, the structural differences can be analyzed in techniques such
as electrophoresis and centrifugation.

Supercoiled DNA may hinder and favor the DNA to unwind and thus affect the interaction
between DNA and other molecules in cells.

Positive and Negative Supercoilings

1. Negative supercoiling is the right-handed coiling of DNA thus winding occurs in the
clockwise direction. It is also known as the "underwinding" of DNA.

2. Positive supercoiling is the left-handed, coiling of DNA thus winding occurs in the
counterclockwise direction. This process is also known as the "overwinding" of DNA.
(CORRECTION FIXED on 10/23/17 - DV, original error had the negative and positive
supercoiling definitions reversed. Also provided more basic clarity to supercoiling).

Prokaryotes and Eukaryotes usually have negative supercoiled DNA. Negative supercoiling is
naturally prevalent because negative supercoiling prepares the molecule for processes that
require separation of the DNA strands. For example, negative supercoiling would be
advantageous in replication because it is easier to unwind whereas positive supercoiling is more
condensed and would make separation difficult.

Topoisomerase

Topoisomerases are enzymes that are responsible for the introduction and elimation of
supercoils. Positive and negative supercoils require two different topoisomerases. This prevents
the distortion of DNA by the specificity of the topoisomerases.The two classes of topoisomerases
are Type I and Type II. Type I stimulates the relaxation of supercoiled DNA and Type II uses the
energy from ATP hydrolysis to add negative supercoils to DNA. Both of these classes of
topoisomerases have important roles in DNA transcription, DNA replication, and recombinant
DNA.

Physical effects of Metal complexes

(i). Unwinding, Shortening, and Bending of the Double Helix

Studies of cis- and trans-DDP binding to DNA employed closed and nicked DNA.

Closed circular DNAs are topologically constrained such that any change in the number of
helical turns must result in an equal and opposite number of superhelical turns. Any reagent that
unwinds the double helix reduces the number of helical turns. Consider, for example, a stretch of
DNA that is 360 base pairs (bp) long. Normal B-DNA has ≈ 10.5 bp per turn or a helical winding
angle of ≈ 34.3° per bp. Suppose the DNA is unwound, so that there are now 12 bp per turn or a
winding angle of ≈ 30°. Instead of 34.3 helical turns (360 ÷ 10.5), the DNA now has only 30
(360 ÷ 12). If this DNA molecule were in the form of a covalently closed circle, the helical
unwinding of -4.3 turns would be accompanied by a superhelical winding of +4.3 turns.

Planar organic dyes such as ethidium bromide (EtdBr) and inorganic complexes such as
[Pt(terpy)(HET)]+ bind to DNA by intercalation, inserting between the base pairs and
unwinding the double helix by ~ 26° per molecule bound

This unwinding can be measured by monitoring changes in the superhelicity of closed circular
DNA. This kind of DNA is subjected to certain topological constraints that lead to the formation
of supercoils and superhelical winding that dramatically alter the hydrodynamic properties of the
DNA. Either gel electrophoresis or analytical ultracentrifugation can be used to measure this
phenomenon. The platinum complexes cis- and trans-DDP also produce changes in the
superhelix density when bound to closed circular DNA. Increasing concentrations of platinum
bound per nucleotide on the DNA first retard its mobility and then increase its mobility through
the gel. These interesting alterations in gel mobility occur because the negatively coiled
superhelix unwinds first into an open, or untwisted, form and then into a positively supercoiled
form. The conformational changes, are directly proportional to the drug-per-nucleotide, or
(D/N)b, ratio. In addition to superhelical winding, both platinum complexes increase the mobility
of nicked circular DNA in the gels. Nicked DNA has one or more breaks in the sugar-phosphate
backbone, which relieve the topological constraint and prohibit the DNA from twisting into
superhelical structures.

What could be the cause of these physical changes in the DNA structure upon cis- or trans-DDP
binding?

It is not Intercalation because…….

Intercalation can be excluded, not only because the compounds do not have the aromatic
character normally associated with intercalators (Figure 9.11), but also through studies of the
manner by which these and other platinum complexes inhibit the intercalative binding of EtdBr
to DNA.89,90 Platinum metallointercalators such as [Pt(terpy)(HET)]+ are competitive
inhibitors of EtdBr binding, as measured by fluorescence Scatchard plots, whereas the non-
intercalators cis- and trans-DDP are not. Moreover, intercalation tends to lengthen and stiffen the
double helix, whereas the mobility changes of nicked circular DNAs upon binding of cis- or
trans-DDP were shown by electron microscopy experiments to arise from a pronounced
shortening of the DNA with increased Pt binding.

One manner by which cis- or trans-DDP might produce these physical alterations in DNA
structure is by kinking( causing twist or curve ) the double helix at or near the binding site. Such
an effect could be produced by the bidentate attachment of platinum; the monofunctional
[Pt(dien)Cl]+ complex does not have these pronounced effects on DNA secondary structure.
Recently, it has been demonstrated that cis-DDP binding to DNA does indeed produce a
pronounced bend in the helix axis. The proof was

a gel-electrophoretic method of analysis that had previously been used to study DNA
bending at naturally occurring specific sequences called A-tracts, consisting of five or six
adenosine nucleosides in a row followed by about the same number of thymidine residues.
 When these d(A5T5)2 sequences are positioned in the center of a DNA restriction
fragment of, say, 150 bp, the mobility of the DNA through polyacrylamide electrophoresis
gels is greatly retarded compared to that of a similar DNA fragment where the A-tract is at
the end. For the former fragment, the bent molecules presumably cannot snake their way
through the pores of the polyacrylamide as well as the molecules whose bends are at the
ends and have little effect on the linear structure. It was further shown that A-tracts bend
the duplex toward the minor groove of the DNA. Moreover, in a DNA containing multiple
A-tracts, the bends must be separated by integral numbers of helical turns (~ 10.5 bp) or
else the effect will cancel and the gel mobility will be that of normal DNA of similar length.
This latter phenomenon has been referred to as phasing.

With this background information in mind, we can now discuss the experiments with cis-DDP
that demonstrated bending.

a 22-bp oligonucleotide (22-mer) containing self-complementary overhanging ends ("sticky

ends") was synthesized with a single cis-diammineplatinum(II) moiety linking adjacent
guanosine residues (Figure 9.15A). A 22-mer was chosen since it has approximately two helical
turns, accounting for some platinum-induced unwinding, and will thus have phased bends when
polymerized. This platinated DNA was then labeled with 32P and treated with the enzyme DNA
ligase, which seals the ends, producing oligomers of the 22-mer having lengths 22, 44, 66, 88,
110, etc., bp. In these oligomers, the platinum atoms are spaced apart approximately by integral
numbers of helical turns. As shown in Figure 9.15, studies of this family of oligomers by gel
electrophoresis revealed a pronounced retardation compared to the mobility of unplatinated DNA
oligomers of comparable size (line P22 in Figure 9.15B). The plots in this figure show the
relative mobilities (RL) of the different length multimers, compared to a control in which the top
strand is not platinated, as a function of the length in base pairs

This experiment unequivocally established that platinum kinks the double helix. As with A-tract-
induced bends, the platinum atoms must be phased in order to induce cooperative bending.
Comparison of the magnitudes of the gel mobility changes made it evident that cis-
{Pt(NH3)2}2+ binding produces a bend comparable to that of two A-tracts, ≈ 34°.

When the platinum atoms are positioned with respect to one another, by exactly integral numbers
of helical turns, the retardation of the DNA multimers in the gel is maximized. This phenomenon
is illustrated in Figure 9.16, where the RL values are plotted as a function of the interplatinum
spacing for oligonucleotides containing the cis-{Pt(NH3)2d(GpG)} intrastrand crosslink. When
the resulting curve was analyzed, the maximum was found to occur at 21.38 bp. Since normal B-
DNA has a helical repeat of 10.5 bp, one can compute the effect of platination from the
expression [(21.38 - 2(10.5)] bp = 0.38 bp. From the fact that one helical turn of DNA comprises
360° and 10.5 bp, the unwinding of the DNA double helix due to the presence of a single cis-
{Pt(NH3)2d(GpG)} intrastrand crosslink can be calculated as
(0.38/10.5)×360=13o.

Biological Consequences of Platinum-DNA Binding

(i). Inhibition of Replication

Binding of cis-DDP to DNA inhibits replication both in vivo and in vitro,

This is shown by a variety of experiments.

Inhibition of replication of SV40 viral DNA in African green monkey cells as a function of the
concentration of added cis-DDP is shown .

(panel A) -SV40 DNA replication as a function of platinum concentration or

(panel C)- SV40 DNA replication as a function of D/N( drug / nucleotide)

In panel B,- D/N is plotted as a function of platinum concentration in the medium.

SV40-infected cells were treated with cis-DDP (●) or trans-DDP (o) at the indicated
concentrations for 40 h. SV40 DNA replication relative to control (untreated) cells was
measured. . Pt in isolated SV40 chromosomes was measured by AAS. The data shown are from a
representative experiment. Experiments were carried out in quadruplicate.

In this experiment, the SV40-infected cells were treated with cisplatin.

After 24 hours, the cells were harvested, and SV40 DNA was isolated; the amount of DNA
synthesis was recorded by comparing with results from control experiments where no platinum
was present.

The data show that, when 25 μM platinum was present, SV40 DNA replication was reduced to
about 5 percent of control. (panel A)

Quantitation reveals that, at ≈ 2 platinum atoms bound per thousand nucleotides (drug-per-
nucleotide, or (D/N)b, = 0.002), DNA synthesis is only 10 percent that of control.
(ii). Mutagenesis and Repair

Apart from inhibition of DNA synthesis, what are the other biological consequences of cisplatin
binding to DNA?

Mutagenesis : One such consequence is mutagenesis, in which a normal base in the sequence is
replaced by a different base. This phenomenon has been demonstrated for cis-DDP-treated cells
in a variety of studies. What brings about such mutagenesis? There are several possibilities. One
is that errors are introduced in DNA strands during attempts of the replication apparatus to
synthesize past a platinum lesion. Another is that the platinum-damaged DNA is recognized by
cellular repair systems that, in attempting to eliminate the platinated stretch of DNA, incorporate
one or more incorrect nucleotides. Platinum-induced mutagenesis can lead to deleterious long-
term health problems in patients treated with cisplatin. It is therefore important to understand the
mechanism by which cellular DNA becomes mutated following platination, and to devise
strategies for minimizing or eliminating this mutagenesis.

DNA Repair : Another biological consequence of cis-DDP binding is DNA repair. Removal of
platinum from DNA by cellular repair mechanisms has been demonstrated by scientists.

For example, in studying cis-DDP-treated human fibroblast cells in culture, it was found that the
amount of bound platinum per nucleotide decreased according to first-order kinetics,

from drug / nucleotide(D/N)b of 2.3 x 10-5 to 3.3 x 10-6 over a six-day period.

Since Pt-DNA adducts are stable with respect to dissociation from DNA under physiological
conditions , loss of platinum was attributed to DNA repair.

Recent studies of in vitro repair of cisplatin-DNA adducts by nuclease enzyme in E. coli, have
provided some details at the molecular level about the process. [32P]-Labeled double-stranded
DNA fragments containing {Pt(NH3)2}2+ adducts at random or defined sites were incubated with
the enzyme. Cleavage of the platinated strand occurred at the 8th phosphodiester bond 5', and the
4th phosphodiester bond 3', to the GG or AG intrastrand crosslink.

(iii). Drug Resistance

Another biological consequence of DNA-platinum interactions, probably related to the repair

phenomenon, is resistance.
Resistance of a cell to a chemotherapeutic agent, which can be inherent or acquired, is a
phenotypical ability of the cell to tolerate doses of a drug that would be toxic to normal, or
parent, cells.

Resistance is often acquired by prolonged exposure of cells in culture to the drug or, in patients,
to repeated doses of drug therapy.

There is not yet any direct proof that platinum-DNA interactions are responsible for acquired
resistance to cisplatin.

Studies of sensitive and resistant tumors in rats have shown, , that after intravenous injection of
10 mg/kg of the drug, the platinum levels were the same after an hour, but after 24 hours a larger
proportion of adducts had been removed in the resistant cells.

Similar results have been found for studies of Pt-DNA adducts in cultured L1210 cells of
varying levels of resistance to cisplatin where, in the 18 h following a 6-hour incubation with the
drug, the resistant cells had up to fourfold more platinum removed than the sensitive cells.

There is evidence that relative amounts of glutathione are increased in cisplatin-resistant cells.
Glutathione presumably uses its thiol moiety to coordinate platinum and diminish the amount
that can bind to DNA.

It is important to inquire what DNA adducts formed by cis-DDP are both cytotoxic and
repairable, what enzymes are responsible for such repair in mammalian cells, by what
mechanisms these enzymes operate, and how this knowledge can be used to design better metal-
based antitumor drugs and chemotherapeutic protocols.

(iv). DNA-protein Interactions

Inhibition of replication, DNA repair, drug resistance, and mutagenesis, probably involve
interaction of a protein or group of proteins with platinated DNA. These interactions are clearly
important in determining the biological consequences of DNA templates containing bound
platinum. Very recent experiments have uncovered the existence of proteins from a variety of
mammalian sources that bind specifically to DNA platinated with cis- but not trans-DDP.
Identifying the nature and function of these factors may provide important clues about the
mechanisms of antitumor activity, drug resistance, or repair. Study of protein-DNA-drug
interactions is an essential feature of the bioinorganic chemistry of platinum chemotherapeutic
agents.

Other Pt Containing Drugs

Information of mechanisms enables the design of new gene therapy strategies and developement
of new and better platinum drugs that will be more potent, produce less side effects, and be
effective against cisplatin-resistant tumours.

The mechanism of action of carboplatin is very similar to that of cisplatin, forming preferrential
cross-links with guanine in DNA thus eventually causing cell death. It may also interact with
nuclear proteins, and is phase-nonspecific.

Like the majority of second generation platinum-based drugs, carboplatin has a lower activity to
that of cisplatin A study has shown that with equimolar doses of carboplatin and cisplatin, the
former was less effective than the latter with respect to ovarian cancer. Comparative studies
have also shown that carboplatin takes longer to bind to the nucleophilic sites of DNA than
cisplatin. Work done at Ohio State University using Raman spectroscopy showed that it would
take three weeks for carboplatin to reach the same level of reaction that cisplatin reached in five
days. This difference in rate indicates that for carboplatin to have the same efficacy as cisplatin, a
larger dose must be given for a longer period of time. A study revealed that a doubling of the
carboplatin dose would not show any significant improvement of pathologic remission or
survival. However, the actual recommended doses of carboplatin may be anywhere from four to
ten times higher than for cisplatin, therefore, it is usually incorporated into high-dose intensity
chemotherapy regimens.

Carboplatin is generally less toxic, with reduced, nephrotoxicity and ototoxicity, however,
nausea and vomiting remain acute,

Carboplatin is nevertheless, still used as an effective anticancer drug, because of its reduced
toxicity and greater ease of administration. It is slowly replacing the use of cisplatin for certain
cancers and situations where toxicity is a crucial factor.

The third most widely available drug related to cisplatin, is oxaliplatin. This compound is
supplied in 50- and 100-mg glass vials, and is reconstituted with sterile water to yield a 2 mg/mL
solution for intravenous administration.. The activity of oxaliplatin has been shown to have a
more powerful pharmacological effect than cisplatin, which is due to its different mechanism of
action. † Studies indicate it attaches onto proteins which are vital for DNA transcription, thus
preventing cell division and causing eventual cell death.

Non Classical Pt anticancer agents

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but
new platinum agents have been very slow to enter the clinic. Recently, however, there has been a
surge of activity, based on a great deal of mechanistic information, aimed at developing
nonclassical platinum complexes that operate via mechanisms of action distinct from those of the
approved drugs.

Despite the clinical success that has been enjoyed by cisplatin,carboplatin, and oxaliplatin,
treatment with these compounds inflicts a number of deleterious side-effects. Among those

affecting patient quality of life are nephrotoxicity, fatigue, In many treatment regimens, one or

more of these side-effects will often be dose-limiting. Another serious limitation of current
platinum-based therapies is that some types of cancer are inherently resistant to treatment and

many others develop resistance with time. The hypothesis that a difference in structure will
result in an altered mechanism of action and, consequently, a different spectrum of anticancer
activity led to the discovery of some non classical Pt anti cancer agents

Other analogues in current clinical use include:

Iproplatin (CHIP) or more formally (cis-dichloro-trans-dihydroxy-cis-

bis(isopropylamine)platinum(IV)), is also less toxic than cisplatin with respect to the degree and
duration of nausea and vomiting, renal toxicity, neurotoxicity and anaemia. ‡ However, it caused
the same cumulative toxicity on haemoglobin, leukocyte count and platelet count, and more
diarrhoea and leukopenia. Iproplatin has similar response rates, duration of response and survival
to that of cisplatin.

Tetraplatin (ormaplatin). Forms intrastrand cross-links but is less cytotoxic than cisplatin.

JM118 (cis-amminedichloro(cyclohexylamine)platinum(II)). This has been shown to form

intrastrand cross-links and have a greater cytotoxicity than cisplatin with respect to human
ovarian carcinoma cells.

JM149 (cis-amminedichloro(cyclohexylamine)-trans-dihydroxoplatinum(IV)). Forms

intrastrand cross-links but is less cytotoxic than cisplatin.

JM216 (bis-acetato-cis-amminedichloro(cyclohexylamine)platinum(IV)). Forms intrastrand

cross-links but is less cytotoxic than cisplatin.
 JM335 (trans-amminedichloro(cyclohexylamine)dihydroxoplatinum(IV)). This has been
shown to have comparable cytotoxicity to cisplatin, because not only is it able to form some
intrastrand cross-links, it is also has the unique ability to form single strand breaks. ‡

Transplatin. This complex is very much lower in cytotoxicity than its cis counterpart,
however, it has been shown to be more kinetically reactive. ¤ The low cytotoxicity was proposed
to be due to fast repairing of its interstrand cross-links.

Some analogues in current development and clinical testing include: ‡

cis-Pt(NH3)(C6H11NH2)(OOCC3H7)2Cl2. This platinum complex has been designed specifically

for oral administration. It is water-soluble, lipophilic and robust enough to survive the gastric
environment. However, as it is a platinum(IV) complex, it will undergo relatively slow ligand
substitution reactions compared with their platinum(II) analogues, therefore, they may have to be
reduced to the kinetically more labile and reactive Pt(II) derivatives in vivo. Many studies have
shown this to be possible, where platinum(IV) metal centers are readily reduced by cellular
components such as glutathione and ascorbic acid to form the platinum(II) analogues that bind
more rapidly to DNA.

Nedaplatin (254S). This cytotoxic drug from Japan has been shown to be active in several
solid tumors without renal toxicity. ‡ The reported dose limiting toxicity is myelosuppression,
especially thrombocytopenia.

Malanato-1,2-diaminocyclohexaneplatinum(II).

5-Sulfosalicylato-trans-(1,2 diaminocyclohexane)Platinum(II) (SSP).

Poly-[(trans-1,2-diaminocyclohexane)platinum]-carboxyamylose (POLY-PLAT).

4-Hydroxy-sulfonylphenylacetato(trans-1,2-diaminocyclohexane)platinum(II) (SAP).

cis-[Pt(NH3)2(pyridine)Cl]+ is much more successful at killing cancer cells .

cis-[Pt(NH3)2(pyridine)Cl]+cation, which came to be called pyriplatin contains only a single
labile chloride ligand and thus, unlike cisplatin, can only form a monofunctional adduct on DNA;
that is, only a single bond can be formed between the platinum center and

a donor atom on DNA. The nature of this adduct was revealed by an X-ray crystallographic
analysis of a dodecamer of site-specifically pyriplatin-platinated duplex DNA . In contrast to the
structure of DNA bearing a cisplatin 1,2-intrastrand cross-link, pyriplatin induced little distortion
of the DNA double helix upon binding.

Pyriplatin displayed a spectrum of activity that differed from that of any of the clinically-
approved platinum drugs . The overall potency of pyriplatin, however, was much less than that of
cisplatin in all cell lines tested.

Phenanthriplatin – A Potent Monofunctional Compound

Phenanthriplatin,was 7-40-times more active than cisplatin in an initial screening of human

cancer cells from a variety of organs. phenanthriplatin showed a spectrum of activity that
differed significantly from that of any other platinum anticancer agents.

The crystal structure of phenanthriplatin revealed the phenanthridine ligand, which is oriented
perpendicular to the platinum coordination plane, to be positioned such that one of the aromatic
C–H groups blocks an open face of the platinum center.

Both phenanthriplatin and pyriplatin, however, react at similar rates with guanosine
monophosphate,

The recent discovery of phenanthriplatin has revealed that monofunctional compounds can
indeed be potent anticancer agents. They distort DNA significantly less than cisplatin, but their
efficacy tracks with transcription inhibition, showing that DNA is their major target. The
spectrum of activity of these compounds is highly differentiated from that of classical platinum
complexes, giving rise to the hope that they might form a class of clinically-relevant drugs. In a
more general sense, these results also validate the exploration of other metal complexes that can
only interact with DNA in a monofunctional manner as anticancer drug candidates.