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SITOSTATIKA

Rennie Puspa Novita, M. Farm. Klin., Apt

ORGANEL SEL

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TERJADINYA KANKER

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SIKLUS SEL

The Mechanisms of Cell Division

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Gambar Siklus Sel

Tahap Mitosis

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DEFINISI SITOSTATIKA

Sitostatika adalah obat yang digunakan untuk mengeblok pertumbuhan sel

kanker dengan cara mempengaruhi metabolisme sel selama siklus sel sehingga
pembelahan sel dan pertumbuhan sel dihambat

Mekanisme aksi dari sitostatika sangat memungkinkan terjadinya efek

karsinogenik, mutagenik dan teratogenik

Diperlukan “Safe Handling

Cytostatic drug” untuk menjamin
keamanan petugas
(Eitel et al, 2000)

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Principles of chemotherapy
Action sites of cytotoxic agents
Antibiotics

Antimetabolites
S
(2-6h)
G2
(2-32h) Vinca
alkaloids

M Mitotic inhibitors
(0.5-2h)
Cell cycle level
Taxoids

Alkylating
agents

G1
(2-∞h)

G0

Titik Kerja Obat Kemoterapi pada siklus sel

Portion of Cell Cycle Drugs

G1 Actinomycin D
Early S Hydroxyurea, 5-fluorouracil, MTX
Late S Doxorubicin, daunomycin
G2 Bleomycin, radiation, etoposide,
teniposide, carboplatin, cisplatin

M Paclitaxel, vincritine, vinblastine

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Spesifitas Kemoterapi thd Fase dan Siklus

Sel

• 1. Semua siklus ( cell cycle non specific )

• Obat anti kanker dpt bekerja pd semua sel, apakah ia sedang

berada dlm siklus pertumbuhan sel atau tidak.

• Pada umumnya sel yg pertumbuhannya cepat lebih sensitif thd

obat daripada yg lambat, hanya perbedaannya tidak terlalu
besar.

Spesifitas Kemoterapi Thd Fase dan Siklus Sel

• 2. Pada siklus pertumbuhan tertentu, pd semua fase ( cell

cycle non phase specific)

• Obat hanya bekerja pd sel yg berada dlm siklus pertumbuhan , ttp tidak pd
sel yg tidak tumbuh (G0).

• Sel yg pertumbuhannya cepat lebih peka terhdp obat dari pada sel yg
lambat, dgn perbedaan kepekaan yg cukup besar. Toksisitas sel tergantung
dari dosis obat & lama paparan (exposure).

• Untuk mendapatkan efek maksimal, sebaiknya obat diberikan secara

intermiten dgn dosis yg tinggi , untuk memberi kesempatan pada sel kanker
yg ada pada fase G0 kembali ke fase G1.

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Spesifitas Kemoterapi Thd Fase dan Siklus Sel

• 3. Pada siklus pertumbuhan tertentu, pada fase tertentu ( cell

cycle phase specific)

• Obat bekerja hanya pd fase tertentu saja dlm siklus

pertumbuhan sel.
• Sel yang pertumbuhannya cepat lebih peka drpd yg
pertumbuhannya lambat, tetapi ada sel yg tidak peka
thd obat walaupun dosisnya tinggi.

• Untuk sel kanker, golongan ini sebaiknya diberi obat

anti kanker dlm waktu yg pendek dan dgn dosis yg
tinggi.

Gambar : “Lokasi “ bekerja obat Sitostatika

Principles of chemotherapy
Action sites of cytotoxic agents
DNA
synthesis Antimetabolites

Cellular level DNA Alkylating agents

DNA transcription DNA duplication

Mitosis
Intercalating
agents
Spindle poisons

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Obat Obat Kemoterapi pada Kanker Ginekologi

3.1.Pembagian dan mekanisme kerja sitostatiska
Table 2 : Useful chemotherapeutic agents
Class and Type Agents
Alkylating agents
Alkyl sulfonate Busulfan
Ethylenimine derivative Thiotepa (triethylenethiophosphoramide
Metal salt Carboplatin, cisplatin, oxaliplatin
Nitrogen mustard Chlorambucil, cyclophosphamide, estramustine, ifosfamide,
mechlorethamine, melphalan

Nitrosourea Carmustine, lomustine, streptozocin

Triazene Dacarbazine, temozolamide
Antimetabolites
Antifolates Methotrexate, pemetrexed, raltitrexed, trimetrexate

Purine analogs Cladribine, clofarabine, fludarabine, mercaptopurine,

nelarabine, pentostatin, thioguanine

Pyrimidine analogs Azacitidine, capecitabine, cytarabine, decitabine, floxuridine,

fluorouracil, gemcitabine

Natural products
Antibiotics Bleomycin, dactinomycin, daunorubicin, doxorubicin,
epirubicin, idarubicin, mitomycin, mitoxantrone, valrubicin

Enzyme Asparaginase
Microtubule polymer stabilizer Docetaxel, paclitaxel
Mitotic inhibitor Vinblastine, vincristine, vindesine, vinorelbine

Topoisomerase I inhibitors Irinotecan, topotecan

Topoisomerase II inhibitors Etoposide, teniposide

Alkylating agents
1.a. Nitrogen mustard
TABLE 3: KEY FEATURES OF SELECTED ALKYLATING AGENTS
Cyclophosphamide Ifosfamide Melphalan BCNU Busul-
(Alkeran) fan
Mechanism of action All agents produce alkylation of DNA through the formation of reactive intermediates that attack nucleophilic sites.

Mechanisms of resistance Increased capacity to repair alkylated lesions, e.g., guanine O6-alkyl transferase (nitrosoureas, busulfan)
Increased expression of glutathione-associated enzymes, including γ-glutamyl cysteine synthetase, γ-glutamyl
transpeptidase, and glutathione-S-transferases
Increased aldehyde dehydrogenase (cyclophosphamide)
Decreased expression or mutation of p53.

Dose/schedule (mg/m2): 400-2,000 IV. 1,000-4,000 IV 8 PO qd × 5 d 200 IV 2-4 mg daily

100 PO qd
Oral bioavailability 100% Unavailable 30% (variable) Not known 50% or greater

Pharmacokinetics: 3-10 (parent) 7-15 (parent) 1.5 (parent) 0.25 to 0.75a (non- 50% or greater
primary elimination 1.6 (aldophosphamide) linear increase with
t½(h) 8.7 (phosphoramide dose from 170-720
mustard) mg/m2)

Metabolism Microsomal hydroxylation Microsomal Chemical Chemical Enzymatic

Hydrolysis to hydroxylation decomposition to decomposition to conjugation with
phosphoramide mustard Hydrolysis to inert dechlorination active and inert glutathione
(active) and acrolein iphosphoramide mustard products, 20-35% products
Excretion as inactive and acrolein excreted unchanged
oxidation products Excretion as inactive in urine
oxidation and
dechloroethylated
products

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Cyclophosphamide Ifosfamide Melphalan BCNU Busul-

fan
Toxicity
Myelosuppression Acute, platelets spared Acute but mild Delayed, nadir at 4 Delayed, nadir 4-6 Acute and
weeks weeks delayed

Alopecia Seen with all alkylating agents

Pulmonary fibrosis
Veno-occlusive disease
Leukemogenesis
Infertility
Teratogenesis

Other Cystitis; cardiac toxicity; Encephalopathy - Hypotension Addisonian

IADH syndrome,
seizures

Precautions Use MESNA with high-dose Always coadminister Decomposes if - Monitor AUC
therapy MESNA administered over with high-dose
<1 hr therapy Induces
phenytoin
(Dilantin)
Drug interactions Expect increased cytotoxicity with radiation %
metabolism
sensitizers and glutathione depletion

aSee reference 276a.

AUC, area under the concentration time curve; BCNU, bischloroethylnitrosourea; IADH, inappropriate antidiuretic hormone syndrome; IV,
intravenously; MESNA, 2-mercaptoethane sulfonate; PO, per os; t½, half-life.

TABLE: KEY FEATURES OF CISPLATIN, CARBAPLATIN DAN OXALIPLATIN

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TABLE 8: KEY FEATURES OF METHOTREXATE SODIUM (MTX)

Mechanism of action Inhibition of dihydrofolate reductase leads to partial depletion of reduced
folates
Polyglutamates of MTX and dihydrofolate inhibit purine and thymidylate
biosynthesis

Metabolism Converted to polyglutamates in normal and malignant tissues. 7-

Hydoxylation in liver
Pharmacokinetics t1/2 α = 2 - 3 h; t1/2 β = 8 - 10 hr
Elimination Primarily as interact drug in urine
Drug interactions Toxicity to normal tissues rescued by leucovorin calcium
L-Asparaginase blocks toxicity and antitumor activity
Pretreatment with MTX increases 5-fluorouracil and cytosine arabinoside
nucleotide formation
Nonsteroidal anti-inflammatory agents decrease renal clearance and
increase toxicity

Toxicity Myelosuppression
Mucositis, gastrointestinal epithelial denudation
Renal tubular obstruction and injury
Hepatotoxicity
Pneumonitis
Hypersensitivity
Neurotoxicity

Precaution Reduce dose in proportion to creatinine clearance

Do not administer high-dose MTX to patients with abnormal renal
function
Monitor plasma concentrations of drug, hydrate patients during high-dose
therapy (see Tables 6.2 and 6.4)

TABLE 11: KEY FEATURES OF 5-FLUOROURACIL

Mechanism of action Incorporation of fluorouridine triphosphate into RNA interferes with RNA synthesis and function.
Inhibition of thymidylate synthase by fluorodeoxyuridylate (FdUMP) leads to depletion of thymidine 5-
monophosphate and thymidine 5- triphosphate, and accumulation of deoxyuridine monophosphate and
deoxyuridine triphosphate.
Incorporation of fluorodeoxyuridine triphosphate and deoxyuridine triphosphate into DNA may affect DNA
stability. Genotoxic stress triggers programmed cell death pathways.

Metabolism Converted enzymatically to active nucleotide forms intracellularly.

DPD catalyzes the initial, rate-limiting step in 5-fluorouracil (5-FU) catabolism.

Antimetabolits -Antagonis Pirimidin : 5 - FU

Pharmacokinetics Primary half-life is 8-14 minutes after IV bolus.
Nonlinear pharmacokinetics from saturable catabolism: Total-body clearance decreases with increasing doses;
clearance is faster with infusional schedules.
Volume of distribution slightly exceeds extracellular fluid space.

Elimination Approximately 90% is eliminated by metabolism (catabolism → anabolism).

<3% and < 10% unchanged drug excreted by kidneys with infusional and bolus 5-FU.
Reduction of 5-FU to dihydrofluorouracil by DPD is rate-limiting. Thereafter: dihydrofluorouracil →
fluoroureidopropionic acid → fluoro-β-alanine.
5-FU and its catabolites undergo biliary excretion.

Pharmacokinetic drug Interference with 5-FU catabolism markedly prolongs its half-life.
Precaution Nonlinear pharmacokinetics: difficulty in predicting plasma concentrations and toxicity at high doses.
Patients with deficiency of DPD may have life-threatening or fatal toxicity if treated with 5-fluoropyrimidines.
Duration of DPD inhibition with eniluracil may be prolonged (8-week washout period recommended).
Patients receiving sorivudine should not receive concurrent 5-fluoropyrimidines (4-week washout period
recommended).
Older, female, and poor-performance-status patients have greater risk of toxicity.
Closely monitor prothrombin time and INR in patients receiving concurrent warfarin DPD, dihydropyrimidine
dehydrogenase.

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Interactions: Inhibitors of DPD:

Thymidine and thymine
Uracil (component of uracil and ftorafur)
5-chloro-2,4-dihydroxypyridine (component of ftorafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate)
3-cyano-2,6-dihydroxypyridine (component of emitefur, 3-{3-[6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl]benzoyl}-1-ethoxymethyl-
5-fluorouracil)
(E)-5(2-bromovinyl)uracil (metabolite of sorivudine)
Eniluracil
Chronic administration of cimetidine (but not ranitidine) may decrease the clearance of 5-FU
Dipyridamole increases 5-FU clearance during continuous i.v. infusion.
Interferon-α may decrease 5-FU clearance in a dose- and schedule-dependent manner.

Biochemical drug interactions
Thymidine salvage via thymidine kinase repletes thymidine 5- triphosphate pools, decreases FdUMP formation, and antagonizes the DNA-
directed toxicity of 5-FU and 5-fluoro-2-deoxyuridine; thymidine may increase fluorouridine triphosphate formation and its incorporation
into RNA.
Sequential methotrexate 5-FU increases 5-FU toxicity and increases fluorouridine triphosphate (FUTP) incorporation into RNA; may
antagonize DNA-directed toxicity of 5-FU.
Leucovorin increases intracellular pools of reduced folates; 5,10-methylenetetrahydrofolate polyglutamates enhance the stability of
reduced folate-FdUMP–thymidylate synthase ternary complex; the magnitude and duration of thymidylate synthase inhibition is
increased.
Inhibitors of de novo pyrimidine synthesis (N-phosphonoacetyl-l-aspartic acid, brequinar) increase 5-FU anabolism to the ribonucleotide
level and 5-FU–RNA incorporation; uridine triphosphate, cytidine triphosphate, deoxycytidine triphosphate, and deoxyuridine
monophosphate depletion may enhance RNA- and DNA-directed toxicity of 5-FU

Toxicity Gastrointestinal epithelial ulceration

Myelosuppression
Dermatologic
Ocular
Neurotoxicity (cognitive dysfunction and cerebellar ataxia)
Cardiac (coronary spasm)
Biliary sclerosis (hepatic arterial infusion of FdUrd)

Precaution Nonlinear pharmacokinetics: difficulty in predicting plasma concentrations and toxicity at high doses.
Patients with deficiency of DPD may have life-threatening or fatal toxicity if treated with 5-fluoropyrimidines.
Duration of DPD inhibition with eniluracil may be prolonged (8-week washout period recommended).
Patients receiving sorivudine should not receive concurrent 5-fluoropyrimidines (4-week washout period recommended).
Older, female, and poor-performance-status patients have greater risk of toxicity.
Closely monitor prothrombin time and INR in patients receiving concurrent warfarin DPD, dihydropyrimidine dehydrogenase.

TABLE 12: KEY FEATURES OF CYTOSINE ARABINOSIDE (ARA-C) PHARMACOLOGY

Mechanism of action Inhibits DNA polymerase α, is incorporated into DNA, and terminates DNA chain
elongation
Metabolism Activated to triphosphate in tumor cells. Degraded to inactive ara-U by
deamination
Converted to ara-CDP choline derivative

Pharmacokinetics Plasma: t1/2α 7-20 min, t1/2β 2 hr; CSF: t1/2 2 hr

Pharmacokinetics Deamination in liver, plasma, and peripheral tissues-100%
Drug interactions Methotrexate sodium increases ara-CTP formation
Tetrahydrouridine, 3-deazauridine inhibits deamination
Ara-C blocks DNA repair, enhances activity of alkylating agents
Fludarabine phosphate increases ara-CTP formation

Toxicity Myelosuppression
Gastrointestinal epithelial ulceration
Intrahepatic cholestasis, pancreatitis
Cerebellar and cerebral dysfunction (high dose)
Conjunctivitis (high dose)
Hidradenitis
Noncardiogenic pulmonary edema

Precaution High incidence of cerebral-cerebellar toxicity with high-dose ara-C in the elderly,
especially in those with compromised renal function

ara-CDP, arabinosylcytosine diphosphate; ara-CTP, arabinosylcytosine triphosphate; ara-U, uracil arabinoside; CSF,
cerebrospinal fluid; t1/2, half-life.

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TABLE 13: KEY FEATURES OF Capecitabine (Xeloda )

Mechanism of action Oral prodrug of 5-FU. That is ultimate converted in tumor tissue to the
active cytotoxic agent 5-FU

Pharmacokinetics Elimination half life 45 minutes, food reduced the rate and extend
absorbtion.It should be administered with water, 30 minutes after meal.
Dosage range 500-3500mg/m2/daydivided 12 hours

Dosage and schedule
For recurrent cervical or epitelial ovarian cancer standard dosing 1500-
2000mg/m2 daily in two divided doses for 2 weeks with a 1 week rest
period (repeat every 3 weeks). For renal insufficiency (CrCl30-
50mL/minutes) modified dose. (CrCL Less than 30) shoul not received
capecitabine.

Toxicity Hematologic: myelosuppression

GI: Diarrhea, vomiting, nausea, stomatitis, abdominal pain, constipation,
dyspepsia.
Dermatologic: Hand and foot syndrome
Hepatic: hyperbilirubinemia

TABLE 14: KEY FEATURES OF Gemcitabine ( Gemzar )

Mechanism of action Actively transported into cells where phosphorylation convert the parent compound into
gemcitabine triphosphate, the active metabolite. Direct inhibition of ribonucleotide reductase
blocks the conversion of ribonucleotides to deoxy ribonucleotides, thus blocking
DNAsynthesis. The active drug is also incorporated into DNA, resultingin strand termination .
in addition, there is inhibition of DNA polymerase. Notable is the fact that the activity of
gemcitabine is not limited to the S phase of cell growth,suggesting that there may be other
unknown mechanism of action.

Pharmacokinetics Minimally protein bound , has high volume of distribution. Peak plasma concentration 30
minutes of drug administration. The half life of the parent compound 1 hour, the active
metabolite can be detectedi n the plasma for up to 24 hours.

Dosage and schedule When given to epithelial ovarian cancer:

Day 1,8,15: 800-1000mg/m2 iv: repeat every 28 days
Day 1,8 : 800- 1000mg/m2 iv: repeat every 21 days
When given to leiomyosarcoma:
Day 1,8 :900 mg/ m2 iv ,repeat every 21 days

Toxicity Hematologic: myelosuppression, particularly trombocytopenia.

GI: Diarrhea, vomiting, nausea, stomatitis, changed in bowel habits.
Dermatologic: radiation recall , maculopapular rash
Hepatic: transaminitis, elevation in bilirubin and alkaline phosphatase.
Renal: hemolytic –uremic syndrome, hematuria, proteinuria.
Pulmonary: ARDS
Neurologic: somnolence, headache
Hypersensitivity:

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TABLE 15: KEY FEATURES OF HYDROXYUREA
Mechanism of action
Pharmacokinetics:
Elimination/metabolism
Drug interactions
Toxicity
TABLE 16: KEY FEATURES OF BLEOMYCIN PHARMACOLOGY
Mechanism of action
Metabolism
Pharmacokinetics
Elimination
Drug interactions
Toxicity
Precaution
23/05/2013
Inhibitor of ribonucleotide reductase by inactivation of the tyrosyl free radical on the M-2
subunit.
Regulation of gene expression.
Nonlinear at high doses.
Bioavailability of essentially 100%.
Elimination half-life of 3.5-4.5 hr.
Rapid distribution to tissues and extracellular fluid compartments
Renal excretion predominates, although interpatient variability is significant.
Several enzyme systems capable of metabolism of HU exist, but the extent of metabolism in
humans is not known.
Increases metabolism of AraC to active metabolite and the incorporation of arabinosylcytosine
triphosphate into DNA.
Enhances the effects of other antimetabolites.
Increases the phosphorylation of antiviral nucleosides and favors their incorporation into viral
DNA.
Enhances effects of ionizing radiation.
Myelosuppression, with white blood cells affected to a greater extent than platelets or red blood
cells.
Gastrointestinal effects (nausea, vomiting, changes in bowel habits, ulceration).
Dermatologic effects (pigmentation, leg ulcers, erythema, rash, atrophy).
Renal effects, rare.
Hepatic effects, occasionally severe.
Neurologic effects, rare.
Acute interstitial lung disease, rare.
Oxidative cleavage of DNA initiated by hydrogen abstraction
Activated by microsomal reduction
Degraded by hydrolase found in multiple tissues
t1/2α: 24 min; t1/2β: 2-4 hr
Renal: 45-70% in first 24 hr
None clearly established at a biochemical level
Oxygen enhances pulmonary toxicity
cis-Platinum induces renal failure and increases risk of pulmonary toxicity
Pulmonary interstitial infiltrates and fibrosis
Desquamation, especially of fingers, elbows
Raynaud's phenomenon
Hypersensitivity reactions (fever, anaphylaxis, eosinophilic pulmonary
infiltrates)
Pulmonary toxicity increased in patients with:
Underlying pulmonary disease
Age >70 yr
Renal insufficiency
Prior chest irradiation
O2 during surgery
Reduce dose if creatinine clearance <80 mL/min
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TABLE 17: KEY FEATURES OF DACTINOMYCIN

Mechanism of action Inhibition of RNA and protein synthesis

Metabolism Unknown
Pharmacokinetics t1/2: 36 hr
Elimination Renal: 6-30%,
Bile: 5-11%
Drug interactions None

Toxicity Myelosuppression
Nausea and vomiting
Mucositis
Diarrhea
Necrosis at extravasation
Radiation sensitization and recall reactions
Precaution Avoid extravasation

TABLE 18: KEY FEATURES OF MITOMYCIN C

Mechanism of action Alkylation of DNA

Metabolism Hepatic

Pharmacokinetics t1/2 α: 2-10 min

t1/2 β: 25-90 min

Elimination Renal: 1-20%

Drug interactions None

Toxicity Myelosuppression
Necrosis at extravasation
Hemolytic uremic syndrome
Interstitial pneumonitis
Cardiomyopathy

Precaution Avoid extravasation

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TABLE 19: KEY FEATURES OF DAUNORUBICIN AND DOXORUBICIN

Mechanism of action Pleiotropic effects including (1) activation of signal transduction pathways, (2) generation of
reactive oxygen intermediates, (3) stimulation of apoptosis, and (4) inhibition of DNA
topoisomerase II catalytic activity

Metabolism Reduction of side-chain carbonyl to alcohol, resulting in some loss of cytotoxicity 2. One-
electron reduction to semiquinone free-radical intermediate by flavoproteins, leading to
aerobic production of superoxide anion, hydrogen peroxide, and hydroxyl radical 3. Two-
electron reduction, resulting in formation of aglycone species that can be conjugated for
export in bile

Pharmacokinetics Doxorubicin: Vd = 25 liters; protein binding = 60-70%; CSF/plasma ratio, very low; t½α =
10 min; t½β = 1-3 hr; t½γ = 30 hr. Circulates predominantly as parent drug; doxorubicinol is
most common metabolite, although a substantial fraction of patients form doxorubicin 7-
deoxyaglycone and doxorubicinol 7-deoxyaglycone; substantial interpatient variation in
biotransformation; no apparent dose-related change in clearance; clearance in men > women.
Daunomycin: Vd, protein binding, and CSF/plasma ratio similar to doxorubicin; t½α = 40
min; t½β = 20-50 hr. Metabolism to daunomycinol faster than for equivalent doxorubicin
metabolism, although interpatient variation remains high.

KEY FEATURES OF DAUNORUBICIN AND DOXORUBICIN

Elimination Only 50 to 60% of parent drug accounted for by known routes of elimination, which include
reduction of the side-chain carbonyl by hepatic aldoketoreductases, aglycone formation, and
excretion of biliary conjugates and metabolites. A substantial fraction of the parent compound
is bound to DNA and cardiolipin in tissues and is slowly dissociated, contributing to
prolonged disappearance. While changes in anthracycline pharmacokinetics may be difficult
to demonstrate in patients with mild alterations in liver function, drug clearance is definitely
decreased in the presence of significant hyperbilirubinemia or patients with a marked burden
of metastatic tumor in liver.

Drug interactions Heparin binds to doxorubicin, causing aggregation; coadministration of both drugs leads to
increased doxorubicin clearance. In rodents, phenobarbital has been shown to increase, and
morphine decrease, doxorubicin disappearance; drugs that diminish hepatic reduced
glutathione pools (acetaminophen and BCNU) sensitize the liver to anthracycline toxicity.

Toxicity 1. Myelosuppression
2. Mucositis
3. Alopecia
4. Cardiac toxicity
5. Severe local tissue damage after drug extravasation

Precaution 1. Acute and chronic cardiac decompensation can occur. Most common is cumulative
dose-related congestive cardiomyopathy, which is more frequent in patients with
underlying hypertensive heart disease or those who have received mediastinal radiation
with a cardiac dose > 2000 cGy.
2. Radiation sensitization of normal tissues, including chest wall and esophagus, is
common and may occur many years after radiation exposure.
3. Extravasation damage to extremities has resulted in loss of limb function.

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TABLE 20 : KEY FEATURES OF THE TAXANES

Paclitaxel Docetaxel

Mechanism of action Low concentrations inhibit microtubule dynamics (dynamic instability and treadmilling).
High concentrations inhibit depolymerization of tubulin

Standard dosage (mg/m2) 175 over 3 hours every 3 weeks 60-100 over 1 hour every 3 weeks
135-175 over 24 hours every 3 weeks (75 is the most common dose used)
80 over 1 hour weekly 36 over 1 hour weekly

Pharmacokinetics and See text

disposition

Principal toxicity Myelosuppression Myelosuppression

Other common toxicities Alopecia Alopecia
Peripheral neurotoxiicty Peripheral neurotoxicity
HSRs Rashes and nail disorders
HSRs (mild to moderate)

Premedication Corticosteroids, H1- and H2-histamine Corticosteroids with each treatment to prevent
antagonists before each treatment to prevent fluid retention;H1-histamine antagonists
HSR (see –administration-) recomemended to HSRs.

Precautions: Patients with abnormal liver function should be treated with caution. See section on dosage and
schedule for specific dosing guidelines.

HSRs, hypersensitivity reactions.

TABLE 21: KEY FEATURES OF THE VINCA ALKALOIDS

Vincristine Sulfate Vinblastine Sulfate Vindesine Sulfate Vinorelbine

Mechanism of action Low concentrations inhibit microtubule dynamics (dynamic instability and treadmilling) High
concentrations inhibit polymerization of tubulin.
Standard dosage 1-1.4 every 3 weeks 6-8 every week 3-4 every 1-2 weeks 15-30 every 1-2 weeks
(mg/m2)

Pharmacokinetics and
disposition

Principal toxicity Peripheral neuropathy Neutropenia Neutropenia Neutropenia

Other common Constipation, SIADH Thrombocytopenia Peripheral neuropathy Peripheral neuropathy

toxicities Alopecia (moderate) (moderate)
Peripheral neuropathy Alopecia Constipation
(mild) Nausea and vomiting
SIADH Diarrhea

Precautions Patients with abnormal liver function should be treated with caution. See section on dosage and
schedule for specific dosing guidelines.
SIADH, syndrome of inappropriate antidiuretic hormone secretion.

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TABLE 22 : DIFFERENTIATION OF HUMAN DNA TOPOISOMERASES

TYPE I AND II
Type I topoisomerase
Monomeric protein, molecular weight ~91 kd
Single-copy gene located on chromosome 20q12-13.2
Transiently breaks one strand of duplex DNA and forms a 3--phospho-tyrosine covalent intermediate
Single-step changes in the linking number of circular DNAs
Its expression is continuous during the cell cycle and in quiescent cells
Mainly involved in relaxation of supercoiled DNA during RNA transcription
ATP independent

Type II topoisomerase
Homodimeric protein, molecular weight 170 kd (isoenzyme IIα) and 180 kd (isoenzyme IIβ)
Single-copy gene located on chromosome 17q21-22 (isoenzyme IIα) and chromosome 3p24
(isoenzyme IIβ)
Breaks both strands of duplex DNA and forms a pair of 5--phosphotyrosine covalent intermediates
Generates a gate through which another region of DNA can be passed
Double-step changes in the linking number of circular DNAs
Its expression increases during S phase of the cell cycle (especially isoenzyme IIα) and is almost
absent in quiescent cells (primarily expression of isoenzyme IIβ)
Involved in DNA replication, recombination, RNA transcription and repair
ATP dependent

TABLE 23 : KEY FEATURES OF TOPOTECAN

Mechanism of action Topoisomerase I poison. Stabilizes the cleavable complex in which topoisomerase I is covalently
bound to DNA at a single-stranded break site. Conversion into lethal DNA damage follows when a
DNA replication fork encounters these cleavable complexes (-fork collision model-).

Metabolism Nonenzymatic hydrolysis of the lactone ring generates the less active open ring hydroxy carboxylic
acid. N-desmethyl metabolite recently characterized in plasma, urine, and feces.
KEY FEATURES OF TOPOTECAN
Pharmacokinetics Approximate terminal half-life of topotecan lactone is 2.9 hr (range, 1.6-5.5 h); approximate
clearance of 62 L/h/m2 (range, 14-155 L/h/m2) reported for 30-min topotecan infusions.

Elimination About 26% to 41% excreted unchanged in urine over 24 h. Concentrated in the bile at levels that are
1.5 times higher than the simultaneous plasma levels
Modifications for organ dysfunction In minimally pretreated patients, no dosage adjustments appear to be necessary for patients with
mild renal impairment (creatinine clearance 40-60 mL/ min), but dosage adjustment to 0.75
mg/m2/d is recommended for patients with moderate renal impairment (20-39 mL/min). Further
dosage adjustments may be necessary for patients with extensive prior chemotherapy or radiation
therapy. Studies of small numbers of patients suggest that dosage adjustments are not required for
hyperbilirubinemia up to 10 mg/dL.

Toxicity Myelosuppression, predominantly noncumulative neutropenia, with thrombocytopenia and anemia

less common
Nausea and vomiting (mild)
Diarrhea (mild)
Fatigue
Alopecia
Skin rash
Elevated liver function test results
Mucositis

Precaution For febrile or severe grade 4 neutropenia lasting >3 d, the dosage for subsequent courses should be
reduced by 0.25 mg/m2/d. Monitoring of blood counts is essential.

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TABLE 24: KEY FEATURES OF IRINOTECAN

Mechanism of action After metabolic activation to 7-ethyl-10-hydroxycamptothecin (SN-38), the mechanism of action is the
same as for topotecan.
Metabolism Irinotecan is a prodrug that requires enzymatic cleavage of the C-10 side chain by an irinotecan
carboxylesterase–converting enzyme to generate the biologically active metabolite SN-38. Both
irinotecan and SN-38 can undergo nonenzymatic hydrolysis of the lactone ring to the open-ring
carboxylate species. Irinotecan can also undergo hepatic oxidation of its dipiperidino side chain to form the
inactive metabolite 7-ethyl-10-[4-N-(5-aminopen-tanoic acid)-1-piperidino]carbonyloxycamptothecin
(APC).

Pharmacokinetics Approximate terminal half-life of irinotecan lactone is 6.8 h (range, 5.0-9.6 h) and approximate clearance is
46.9 L/h/m2 (range, 39.0-53.5 L/h/m2). Approximate terminal half-life of SN-38 lactone is 11.05 h (range,
9.1-13.0 h).
Elimination Elimination of irinotecan occurs by urinary excretion, biliary excretion, and hepatic metabolism. About
16.1% (range, 11.1-20.9%) of an administered dose of irinotecan is excreted unchanged in the urine. SN-
38 is glucuronidated, and both the conjugated and unconjugated forms are excreted in the bile. SN-38
glucuronide can also be detected in plasma.
Modifications for organ dysfunction No definite recommendations are available for patients with impaired renal or hepatic dysfunction.
Extreme caution is warranted in patients with liver dysfunction or Gilbert's disease.
Toxicity Early-onset diarrhea within hours or during the infusion associated with cramping, vomiting, flushing, and
diaphoresis. Consider atropine 0.25-1.0 mg s.c. or i.v. in patients experiencing cholinergic symptoms. Late-
onset diarrhea can occur later than 12 h after drug administration.
Myelosuppression, predominantly neutropenia and less commonly thrombocytopenia.
Alopecia
Nausea and vomiting
Mucositis
Fatigue
Elevated hepatic transaminases
Pulmonary toxicity (uncommon) associated with a reticulonodular infiltrate, fever, dyspnea, and
eosinophilia

Precaution Severe delayed-onset diarrhea may be controlled by high-dose loperamide given in an initial oral dose of 4
mg followed by 2 mg every 2 h during the day and 4 mg every 4 h during the night. High-dose loperamide
should be started at the first sign of any loose stool and continued until no bowel movements occur for a
12-hr period. Particular caution is also warranted in monitoring and managing toxicities in elderly patients
(>64 yr) or those who have previously received pelvic/abdominal irradiation.

TABLE 25 : KEY FEATURES OF EPIPODOPHYLLOTOXIN DERIVATIVES

Etoposide (VP-16) Teniposide (VM-26)

Mechanism of action Inhibition of Top2, Same but ≈ 10-fold more

Nonintercalator potent

Pharmacokinetics Terminal half-life = 6-8 hr Terminal half-life = 9.-21 hr

Elimination Hepatic metabolism, Renal Probable hepatic metabolism

excretion 35-40%

Toxicities Neutropenia, Same as etoposide

Thrombocytopenia, (mild)
Alopecia, Hypersensitivity,
Mucositis (high doses)

Precautions Reduced dose proportionate to Possible increased toxicity in

creatinine clearance hepatic failure

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KEMOTERAPI TUNGGAL atau KOMBINASI ?

Penggunaan Kemoterapi Tunggal mempunyai beberapa

keterbatasan :
1. Efek samping toksisitas membatasi dosis dan lama-
nya pemberian obat, sehingga juga membatasi daya
bunuh terhadap sel kanker.
2. Daya tahan hidup sel dan pembelahan kembali dari
sel kanker menyebabkan terbentuknya tumor padat
yang tidak bisa dicapai kemoterapi.
3. Terjadinya resistensi obat secara spontan.
4. Menyebabkan resistensi multiple dari beberapa
kemoterapi.

Faktor-faktor yang penting pada pemakaian Kemoterapi

Kombinasi :
1. Masing-masing obat harus poten sebagai anti kanker
secara tunggal.
2. Obat-obat harus mempunyai titik tangkap yang ber-
beda pada siklus sel sehingga mencegah resistensi.
3. Obat-obat tersebut harus mempunyai kerja yang
sinergistik, dan tidak saling melemahkan.
4. Obat-obatan yang dipilih mempunyai efek samping
pada sistim organ yang berbeda.
5. Masing-masing obat harus diberikan secara intermit-
ten sehingga memperkuat daya bunuh sel dan daya
immunosupresinya minimal.

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EFEK SAMPING OBAT

1. Sistim Hemopoetik :
* Pansitopeni.
2. Sistim Gastrointestinal :
* Mual muntah, diare.
* Stomatitis.
* Perdarahan saluran cerna.
* Enterocolitis.
3. Immunosupressi.
4. Pada kulit :
* Reaksi alergi, iritasi, sampai Steven Johnson
Syndrome.
* Alopecia.
5. Pada Hati :
* Drug induced hepatitis.

6.Pada Paru-paru :
* Interstitial pneumonitis.
7. Pada Jantung :
* Kardiomiopati.
8. Pada Saluran Kencing :
* Chronic azotemia
* Acute renal failure
* Retensi cairan.
9. Pada Sistim Saraf :
* Neuropati.
10. Pada Pembuluh Darah :
* Kerusakan pembuluh darah.

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11. Terjadinya keganasan sekunder :

* Leukemia
12. Pada Gonad :
* Amenorrhoe.
* Kegagalan fungsi ovarium.
Infertilitas.
13. Gangguan Metabolik :
* Hiponatremi
* Hiperurisemi
* Hipokalsemi.

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PENGALAMAN PENGOBATAN
KANKER GINEKOLOGIS DENGAN SITOSTATIKA
DI DIVISI ONKOLOGI - GINEKOLOGI
RSUD Dr SOETOMO - SURABAYA

I. KANKER SERVIKS
a. Bleomycin + Mitomycin
b. B O M (Bleomycin + Oncovin + Mitomycin)
c. P V B (Cisplatin + Vincristin + Bleomycin)
d. Paclitaxel- cisplatin/ carboplatin
e. Cisplatin ( paliatif, radiosensitizer)

II. KANKER OVARIUM

1. Kanker Ovarium yang berasal dari Epitel :
a. CP
b. CAP
c. Paclitaxel + Carboplatin
d. Docetaxel+ Carboplatin
e. Gemzar
f. Xeloda

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2. Kanker Ovarium yang berasal dari Germ Cell :

a. VAC (Vincristin + Actinomycin + Cycloph.

b. PVB (Cisplatin + vincristin + Bleomycin)

c. PEB

III. PENYAKIT TROFOBLAS

1. Penyakit Trofoblas Jinak :
* Pada Mola Hydatidosa diberikan MTX
profilaksis ( kontroversi).
* Diberikan injeksi MTX 0,4 mg/kgBB hari (IM) selama
5 hari
* Evaluasi klinis dan kadar β HCG minimal
sampai 8 minggu setelah kuret kedua.

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2. Penyakit Trofoblas Ganas :

a. Resiko Rendah
* Methotrexate atau Actinomycin D dosis
tunggal.
b. Resiko Sedang
* kombinasi MTX + Actinomycin.
* kombinasi MTX + Actinomycin +
Chlorambucil.
* kombinasi Etoposide + MTX + Actino.
c. Resiko Tinggi
* EMACO (etoposide + MTX + Actino. +
Cycloph. + Oncovin).

IV. KANKER ENDOMETRIUM

a. Cyclophosphamide.

b. Doxorubicin.

c. Kombinasi Cyclo. + Doxo.

d. Hormonal (Progesteron).

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