3. Sir Kenneth was Chief Medical Officer for Scotland and
for England, and is now the Vice-Chancellor of the
University of Durham
Get big cell kill from fluorouracil,
be a medicine man with melphalan,
keep things pristine with vincristine,
shout with glee with 6MP…
but, and this is important for today,
you can flatten ’em, with platinum
Witness Seminar held by the Wellcome Trust Centre
for the History of Medicine at UCL, London, on 4
April 2006
4. History of Cisplatin
The compound cis-PtCl2(NH3)2 was first described by M.
Peyrone in 1845, and known for a long time as Peyrone's salt.
The structure was deduced by Alfred Werner in 1893.
In 1965, Barnett Rosenberg, van Camp et al. of Michigan State
University discovered that electrolysis of platinum electrodes
generated a soluble platinum complex which inhibited binary
fission in Escherichia coli (E. coli) bacteria. Although bacterial
cell growth continued, cell division was arrested, the bacteria
growing as filaments up to 300 times their normal length.
Cisplatin was approved for use in testicular and ovarian cancers
by the U.S. Food and Drug Administration on December 19,
1978.
13. PROPRIETÀ CHIMICHE CHE GOVERNANO L’ATTIVITÀ CLINICA DEI COMPLESSI DEL PLATINO
carrier ligands
leaving groups
1. Configurazione
2. Stato di ossidazione
3.Natura dei gruppi uscenti (leaving groups)
4. Natura dei carrier ligands
14. Chimica del cisplatino in soluzione acquosa
Cl Cl OH 2
H 3N Pt Cl H 3N Pt OH 2 H 3N Pt OH 2
NH 3 NH 3 NH 3
reattivo nella cellua
m ajor groov e
m ajor groove
m a jo r g ro o v e
Cl
G Cl G H 3N G
H 3N Pt OH 2 + G Pt G Pt
H 3N
NH 3 H 3N G
NH 3
19. Action of Cisplatin
Cisplatin coordinates to DNA and that
this coordination complex not only
inhibits replication and transcription of
DNA, but also leads to programmed cell
death (called apoptosis)
25. • In vitro studies on both prokaryotic and
eukaryotic cells revealed that DNA adducts
of both cisplatin and trans-DDP blocked the
action of DNA polymerase
• In vivo studies showed that cisplatin and
trans-DDP inhibited replication equally well
• DNA replication is not the only factor
important for the clinical activity of cisplatin
26. The cytotoxic activity of cisplatin may
arise from the cell’s inability to repair
DNA damage caused by cisplatin.
27. • The cell detects DNA damage by the
action of damage recognition proteins
• HMG-domain proteins bind cisplatin–
DNA adducts in vitro
• In vivo assays on yeast shown that HMG-
domain proteins are important for the
activity of cisplatin:
• These effects may also be in operation in
mammalian cells
28. Role of HMG domain proteins
1. HMG domain containing transcription
factors bind preferentially to the
cisplatin–DNA adducts, they could
wreak havoc with the transcriptional
machinery
2. When HMG domain proteins bind to
the cisplatin–DNA adducts, the
adducts would not be recognized by
the repair machinery
42. Cisplatin Administration
• Mixed in 250 - 1000 ml NS
• Mixed with 2 – 4 grams magnesium sulfate in
same bag
• Infused over atleast 2 hours
• Pre-hydration of 250 – 1000 mL NS depending
on dose
– ensure adequate UOP (> 200 cc/2 hours)
– Caution in patients with HF or CRI who
cannot tolerate this amount of fluids
– May require furosemide IVP
• Post-hydration with 1 Liter NS
– instruct patient to drink 6 – 8 full glasses of
water/day (1.5 – 2 Liters/day) at home
43.
44. CISPLATIN TOXICITY
• Nausea and vomiting
– acute or delayed
– highly emetogenic if use doses than 50 mg/m2
– moderately emetogenic if use doses 50 mg/m2
– severe if not adequately prevented with appropriate
medications
– typical anti-emetic regimen
• aprepitant 125 mg po day 1 then 80 mg po days 2 – 3
• dexamethasone 12 mg po day 1 then 8 mg po daily x 3
days
• palonosetron 0.25 mg IVP day 1
• metoclopramide 10 mg every 4 hours prn N/V
45. CISPLATIN TOXICITY
• HEMATOLOGIC TOXICITY
– can affect all 3 blood lineages
– minor neutropenia, thrombocytopenia, and ANEMIA
– its mild hematologic toxicity has allowed its
combination with highly myelosuppressive
chemotherapy
• OTOTOXICITY
– audiograms show bilateral and symmetrical high
frequency hearing loss
– usually irreversible
– caution with other drugs (aminoglycosides)
46. CDDP-INDUCED ORGAN
TOXICITY
* Nephrotoxicity
* Neurotoxicity
* Cardiomyopathy
47. CDDP CARDIOMYOPATHY
1- Electrocardiographic changes
2- Myocarditis
3- Arrythmia
4- Congestive heart failure
5- Bradycardia
6- Lethal cardiomyopathy when CDDP
is given in combination chemotherapy
protocols containing MTX, 5-FU, BLM, and
DOX
48. CISPLATIN TOXICITY
• Neurotoxicity
– dose-limiting toxicity
– most common symptoms are peripheral neuropathy and
hearing loss
– less common include Lhermitte’s sign (electric shock-like
sensation transmitted down the spine upon neck flexion)
– autonomic neuropathy, seizures, encephalitic symptoms, and
vestibular disturbances
– cumulative doses > 300 mg/m2
– first signs are loss of vibration sensation, loss of ankle jerks
and painful paresthesias in hands and feet
– proximal progression and deficits in proprioception, light touch
and pain
– recovery is typically incomplete
49. CISPLATIN TOXICITY
• Nephrotoxicity
– dose-limiting toxicity
– renal damage is usually reversible but rarely can be
irreversible and require dialysis
– platinum concentrations are higher in the kidney than in the
plasma or other tissues
– initiating event is proximal tubular lesion
– secondary events such as disturbances in distal tubular
reabsorption, renal vascular resistance, renal blood flow, and
glomerular filtration, and polyuria seen 2 to 3 days later
– hypomagnesemia develops in about 75% of patients,
beginning 3 to 12 weeks after therapy and persisting for
months to years
54. CISPLATIN NEPHROTOXICITY
• Preventive Measures
– aggressive saline hydration (enhance urinary
excretion)
– lower doses may require less hydration
– infuse over 24 hours
– pretreatment with amifostine
– avoid other nephrotoxic agents
– magnesium supplementation
– predisposing factors to developing nephrotoxicity
include age 60 years or older, higher
doses, pretreatment GFR < 75 ml/min, cumulative
dose, low albumin, single dose compared with daily
x 5 administration schedules
55.
56.
57. Drug Interactions
DRUG INTERACTIONS
• Phenytoin ... decreased epilepsy control
• Frusomide, hydralazine, diazoxide &propranolol
increased nephrotoxicity
• Dose adjustment of Allopurinol & colchicine doses
needed due to hyperuricemia of Cisplatin
• Antihistamines mask ototoxicity of cisplatin
• Cephalosporins Abs e.g. Cephalexin
& Aminoglycosides Abs e.g. Gentamycin
increased nephrotoxicity
• Live attenuated vaccines are contraindicated
57
63. CLINICAL PHARMACOLOGY OF
CARBOPLATIN
•Both carboplatin and cisplatin exert their
therapeutic effects primarily by forming intrastrand
DNA adducts with adjacent guanine residues in
tumor-cell DNA .
• Although the platinum-containing moieties of
carboplatin and cisplatin are identical , it is the
unique leaving groups of each that ultimately
facilitate DNA binding.
• In the case of carboplatin,the carboxylate groups
are much more stable adducts than the chloride
groups of cisplatin. This decreases the chemical
reactivity of carboplatin relative to cisplatin and
significantly lengthens the time required for its
aquation and subsequent DNA-adduct formation .
64. CARBOPLATIN
• IV NORMAL SALINE.
• DOSING-mg/m2×min(AUC).
• DOSE-4,5,or6mg/m2×min,in 250ml NS,
3-4 weeks.
• INFUSION TIME- 1hr-4hr.
• LESS NEPHROTOXIC, MORE
MYELOTOXIC
65. •Carboplatin is excreted almost exclusively
by the kidneys.
•The total body clearances of ultrafiltrable
platinum and that of the parent carboplatin
molecule are roughly equivalent and
correlate linearly with the pretreatment
glomerular filtration rate (GFR).
•Approximately 65%-70% of the total
platinum dose is eliminated as intact
carboplatin in the urine during the first 12-16
hours after administration, while the
remaining 30%-35% of the dose, which is
protein-bound and inactive, is eliminated
slowly over the next five days
66. CALVERT’ S FORMULA
Total dose (mg) = target AUC (mg/ml ´ min)
´ (GFR [ml/min] + 25)
The value of 25 ml/min is a constant that used to
correct for the nonrenal clearance of irreversibly
tissue-bound carboplatin .
67.
68.
69.
70.
71.
72. CARBOPLATIN TOXICITY
• Moderately emetogenic
• Renal impairment is rare
– because it is excreted primarily in the kidneys as an
unchanged drug, it is not directly toxic to the renal tubules
• Neurotoxicity is rare
• Myelosuppression
– especially THROMBOCYTOPENIA
– dose-limiting toxicity
– cumulative
• Hypersensitivity reaction
– thought to be due to type I hypersensitivity (IgE mediated)
– incidence of hypersensitivity seems to be correlated with
increased number of cycles of carboplatin administered
– risk of hypersensitivity due to carboplatin exposure
significantly increases during the sixth cycle, and it continues
to increase up to cycle 8
74. •Oxaliplatin differs from cisplatin in that the
amine groups of cisplatin are replaced by
diaminocyclohexane (DACH).
• The molecular weight of oxaliplatin is
397.3.
• It is slightly soluble in water, less so in
methanol, and almost insoluble in ethanol
and acetone .
• Its full chemical name, oxalato(trans L- 1,2
diaminocyclohexane)platinum, refers to the
presence of an oxalate “leaving group” and
the DACH carrier ligand, which are
responsible, at least in part, for its unique
properties
75. OXALIPLATIN
• IV IN 5%DEXTROSE.DOSING IN mg/m2
• DOSE-85-130mg/m2 ,2-3weeks
• INFUSION TIME-6hr, but 2hr and 4 hr is
used.
• COLORECTAL CANCER
76. Oxaliplatin Toxicity
• Gastrointestinal
– Moderate emetogenicity
– diarrhea
• Minimal hematologic toxicity
– Thrombocytopenia is dose-related (doses > 135 mg/m2)
– mild neutropenia
– mild anemia
• No nephrotoxicity
• Hypersensitivity reaction
– mild
– generally subside upon discontinuation
– slowing down infusion rate and giving an antihistamine and/or
steroid
– desensitization protocol
• Peripheral neuropathy
– Prevention: Stop and Go Strategy, Ca and Mg infusions (may
compromise efficacy)
77. Clinical characteristics of oxaliplatin neurotoxicity
Acute symptoms Chronic symptoms
• Common (90% of patients) • 10% to 15% moderate
• May appear at first treatment cycle neuropathy after a cumulative
• Generally mild dose of 780 to 850 mg/m2
• Onset during or within hours of • Does not seem to be
infusion schedule-dependent
• Transient, short lived • Dysesthesias and
• Cold-triggered or cold-aggravated paresthesias persisting
• Dysesthesias and paresthesias between cycles
• Manifesting as stiffness of the • Progressively evolving to
hands or feet, inability to release functional impairment:
grip, and sometimes affecting the difficulties in activities
legs or causing contractions of the requiring fine sensorimotor
jaw coordination, sensory ataxia
• Distal extremeties, perioral, oral, • Tends to improve/recover
and pharyngolaryngeal areas after treatment is stopped
• Depending on dosing schedule • Spares motor neurons (like
(infusion rate) cisplatin)
78. OXALIPLATIN NEUROPATHY
Supportive care for prevention of oxaliplatin induced
neuropathy
avoid cold temperatures
if exposure to cold temperatures cannot be
avoided, such as use of the refrigerator,
wear gloves during the exposure
use scarves and face masks in cold weather
prolonging the infusion time
use cotton socks, pot holders, rubber gloves
for dish washing
assess the water temperature in the home
use moisturizer
82. SATRAPLATIN
A novel oral platinum compound
Activity against cell lines resistant to taxane
and other platinum compounds
bis-(acetato)-ammine dichloro-(cyclohexylamine) platinum IV
83. Proposed Indication
Orplatna® (satraplatin capsules) is indicated for
the treatment of patients with androgen
independent (hormone refractory) prostate
cancer that has failed prior chemotherapy.
85. Satraplatin and Prednisone Against
Refractory Cancer
SPARC Trial (n=912)
R
A Satraplatin 80 mg/m2/d x 5 po q5wks
Progressive N + Prednisone 5 mg x 2/daily Q 35 days
HRPC D
O
1 prior M
chemo Placebo + Prednisone
I
5 mg x 2/daily Q 35 days
Z
E
2:1
1° Endpoint: 30% increase in TTP with 85% power
2° Endpoints: OS, time to pain progression
J.Bellmunt 09/2008
