PLATINUM COMPOUNDS

9/10/2012

DR. R. RAJKUMAR III YR POST GRADUATE DEPARTMENT OF MEDICAL ONCOLOGY

Derivati del platino

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

Sir Kenneth was Chief Medical Officer for Scotland and for England, and is now the Vice-Chancellor of the University of Durham

Witness Seminar held by the Wellcome Trust Centrefor the History of Medicine at UCL, London, on 4 April 2006

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.

History of Cisplatin

Barnett Rosenberg(1961)

• To study the effect of electric fields on Cell Division (like Mitosis)

• Started with Escherichia coli bacterial cells

Idea !

V

Anodo di Pt

catodo di Pt

batteri medium

L’esperimento di Rosenberg

THE PLATINUMS

PROPRIETÀ CHIMICHE CHE GOVERNANO L’ATTIVITÀ CLINICA DEI COMPLESSI DEL PLATINO

1. Configurazione2. Stato di ossidazione

leaving groups

3.Natura dei gruppi uscenti (leaving groups)

carrier ligands

4. Natura dei carrier ligands

reattivo nella cellua

Chimica del cisplatino in soluzione acquosa

NH3

PtH3N OH2

Cl

NH3

PtH3N Cl

Cl

NH3

PtH3N OH2

OH2

NH3

PtH3N OH2

Cl

G

G+

major groove

NH3

PtH3N

Cl

G

G

major groove

H3NPt

H3N

G

G

major groove

Addotti del cisplatino con il DNA

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)

Action of Cisplatin

Cisplatin in cell level

Binding site in Base Pairs…

Geometrical Isomer

• 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

The cytotoxic activity of cisplatin may arise from the cell’s inability to repair DNA damage caused by cisplatin.

• 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

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

Role of HMG domain proteins

DNA-Cisplatin-HMG adduct

INDICATIONS

• NSCLC• SCLC• AERODIGESTIVE TRACT

MALIGNANCIES• LOWER G.I. MALIGNANCIES• GYNECOLOGIC MALIGNANCIES• GENITOURINARY MALIGNANCIES• HEAD&NECK CANCERS

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

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

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)

CDDP-INDUCED ORGAN TOXICITY

* Nephrotoxicity

* Neurotoxicity

* Cardiomyopathy

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

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

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

CISPLATIN NEPHROTOXICITY

CISPLATIN NEPHROTOXICITY

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

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

CISPLATIN RESISTANCE

Putative Mechanisms of Cisplatin Resistance

1

2

3

4

5

6

Kartalou, 2001

CARBOPLATIN

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 .

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

•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 theremaining 30%-35% of the dose, which is protein-bound and inactive, is eliminated slowly over the next five days

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 .

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

OXALIPLATIN

•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

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

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)

Clinical characteristics of oxaliplatin neurotoxicity

Acute symptoms Chronic symptoms

• Common (90% of patients)• May appear at first treatment cycle• Generally mild• Onset during or within hours of

infusion• Transient, short lived• Cold-triggered or cold-aggravated• Dysesthesias and paresthesias• Manifesting as stiffness of the

hands or feet, inability to release grip, and sometimes affecting the legs or causing contractions of the jaw

• Distal extremeties, perioral, oral, and pharyngolaryngeal areas

• Depending on dosing schedule (infusion rate)

• 10% to 15% moderate neuropathy after a cumulative dose of 780 to 850 mg/m2

• Does not seem to be schedule-dependent

• Dysesthesias and paresthesias persisting between cycles

• Progressively evolving to functional impairment: difficulties in activities requiring fine sensorimotor coordination, sensory ataxia

• Tends to improve/recover after treatment is stopped

• Spares motor neurons (like cisplatin)

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

COMPARISON OF PLATINUM TOXICITY

Table 5. Comparative adverse effect profiles of platinum drugs

Adverse effect cisplatin carboplatin oxaliplatin

Nephrotoxicity ++ + -

Gastrointestinal toxicity

+++ + +

Peripheral neurotoxicity

+++ - ++

Ototoxicity + - -

Hematologic toxicity + ++ +

Hypersensitivity - + -

DISEASE COMPARISONS OF PLATINUM ANALOGUES

• OVARIAN CANCER- CLINICAL EQUIVALENCY FOR CDDP & CARBO

• TESTICULAR CANCER- SUPERIORITY FOR CDDP

• NSCLC- CDDP MAY OFFER IMPROVED EFFICACY

• SCLC- CARBO EQUAL EFFICACY & LESS TOXIC

• COLORECTAL CANCER –OXALIPLATIN STRONGLY SUPERIOR

DISEASE COMPARISONS OF PLATINUM ANALOGUES

• CERVIX CANCER- CDDP – OPTIMAL RADIOSENSITIZER. CARBO-ACTIVE

• GASTRIC CANCER-CDDP SUPERIOR, OXALIPLATIN EQUIVALENT

• ESOPHAGEAL CANCER- CDDP OPTIMAL RADIOSENSITIZER. CARBO-ACTIVE

• HEAD&NECK CANCER- CDDP OPTIMAL RADIOSENSITIZER.CARBO ACTIVE.

SATRAPLATIN

A novel oral platinum compound Activity against cell lines resistant to taxane

and other platinum compounds

bis-(acetato)-ammine dichloro-(cyclohexylamine) platinum IV

Proposed Indication

Orplatna® (satraplatin capsules) is indicated for the treatment of patients with androgen independent (hormone refractory) prostate cancer that has failed prior chemotherapy.

SATRAPLATIN

• ORALLY 5 TIMES DAILY.• DOSING –mg/m2.• DOSE- 80mg/m2/day D1-D5.• PROSTATE CANCER.

Satraplatin and Prednisone Against Refractory Cancer

SPARC Trial (n=912)

Progressive HRPC1 prior chemo

Satraplatin 80 mg/m2/d x 5 po q5wks+ Prednisone 5 mg x 2/daily Q 35 days

Placebo + Prednisone 5 mg x 2/daily Q 35 days

1° Endpoint: 30% increase in TTP with 85% power 2° Endpoints: OS, time to pain progression

2:1

RANDOMIZE

J.Bellmunt 09/2008

Progression Free Survival100

0

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0 10 20 30 40 50 60 70 80 90

Weeks

Su

rviv

al P

rob

ab

ilit

y (

%)

Satraplatin + Prednisone

Placebo + Prednisone

HR: 0.67 (95% CI: 0.57 - 0.77)

Log-Rank P = 0.0000003

S PMedian (wks) 11.1 9.7

J.Bellmunt 09/2008

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