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CYTOSTATICS Martínková, 2005
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Action - toxicity Most drugs used in cytostatic
chemotherapy interfere with the synthesis of DNA
and /or RNA, with the results that cell death
occurs or cell multiplication ceases. These
effects are not confined to malignant cells-
most cytostatic agents are also toxic to normal
dividing cells, particularly those in bone
marrow, the GIT, gonads, hair follicles and
skin.
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General principles in the use cytostatics
interfere with several different stages of the
cell cycle and so open the way to the rational
use of drug combinations. Cycle non-specific
drugs act at all stages in the proliferating
cell cycle (but not in the G0 resting
phase) Phase-specific drugs act only at a
specific phase the more rapid the cell turnover
the more effective they are.
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The cell cycle and the phase specificity of some
cytotoxic drugs.
G0 resting phase G1 prereplicative phase G2
postoperative phase S DNA synthesis M mitosis
or cell division
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• Adjuvant therapy
• courses of cytostatic drugs are given when the
  cancer has apparently been destroyed by surgery
  or radiotherapy.
• Its objective is to eradicate micrometastases.
• Neoadjuvant therapy
• is defined as a preoperative cytostatic
  treatment,
• in patients with locally advanced solid tumors
• the aims of neoadjuvant chemotherapy
  radiotherapy are
• the potentiality of curative resection,
• the reduction of surgical measures, and
• an increase in life span.

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Can we decrease toxicity? Bone marrow
suppression and autologous stem cell support
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Dose-response/toxicity curves demonstrating the
potential therapeutic benefit of autologous stem
cell support. (Kuhlmann 1996)

Increase in therapeutic effect
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• RESISTANCE
• primary (non-responsive tumors)
• aquired
• reduced uptake of drugs
• deletion of enzyme to activate drug
• increased detoxication of drug
• increased concentration of target enzyme
• rapid repair of drug-induced lesion
• decreased number of receptors for drug
• increased efflux
• 
  

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Mechanisms of cellular drug resistance
? deletion of enzyme to activate drug
? increased detoxication of drug
? reduced uptake of drugs
?
active metabolite
inactivated cytotoxic drug
C
? increased efflux (multidrug resistance)
defective cellular target
T
rapid repair of drug-induced lesion
T
increased concentration of target molecules
T- cellular target T - gene amplification
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• 1. ALKYLATING AGENTS
• 2.ANTIMETABOLITES
• a. folic acid antagonists-MTX
• b. pyrimidine antagonists - 5 FU, ara-C
• c. purine antagonists - 6-MP, 6-TG

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3. PLANT ALKALOIDS etoposide, Vinca alkaloids,
paclitaxel 4. ANTIBIOTICS doxorubicin,
daunorubicin, bleomycin 5. HORMONES
estrogens, aminoglutethimide, progestogens,
glucocorticosteroids 6. PLATINUM COMPOUNDS
cisplatin,carboplatin 7. MISCELLANEOUS AGENTS
procarbazine 8. INTERFERONS
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• 1. A L K Y L A T I N G AGENTS cyclophosphamide,
  
• ifosphamide, chlorambucil, nitrosoureas
• cycle-nonspecific drugs
• combine with DNA of both malignant and normal
  cells and
• thus damage not only malignant cells but also
  dividing normal
• cells (the bone marrow and the GIT)
• mechanisms the alkyl groupings (ethyleneimine
  ions and
• positively charged carbonium ions) are highly
  reactive, so that
• combine with susceptible groups in cells and in
  tissue fluids
• (SH, PO4)
• ? The alkylating action on DNA leads to abnormal
  base
• pairing or intra and interstrand links with
  DNA molecule
• cytotoxic, mutagenic and teratogenic effects may
  result
• from interaction swith DNA

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Cyclophosphamide an inactive prodrug
can be given orally ? is activated
by the CYP450 in liver as well as in tumors. ?
with time, the active metabolite and also
acrolein are formed. The latter compound
is responsible for bladder toxicity
(chemical hemorrhagic cystitis). ? a wide
spectrum antitumor and immunosuppressive
activity ? used as a part of combination therapy
regimens to treat lymphoma, breast cancer,
bladder cancer, ovarian cancer
and various children
malignancies
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T o x i c i t i e s ? bone marrow depression,
granulocytopenia, thrombocytopenia. ?
urotoxicity appears with chronic therapy - M
e s n a dimesna (2-mercaptoethane sulfonate
sodium) protects the urinary tract against
the irritant effects by supplying
sulfhydryl groups to form a stable thioether with
acrolein. Mesna is given by IV injection or
by mouth The nitrosoureas carmustine and
lomustine are potent bone marrow toxins.
Hepatotoxicity and nephrotoxicity. Broad
spectrum of activity (solid tumors, in
particular brain tumors).
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• 2. A N T I M E T A B O L I T E S
• are structural analogues of cellular metabolites
  
• their selectivity for malignant cells is only
  partial.
• usually phase specific as their action is
  confined to
• specific steps in the synthesis of nuclear
  material.
• a. F o l i c a c i d antagonists
  (antifolates)
• Methotrexate (MTX) is a congener of folic acid
  (FA).
• FA is required in the synthesis of thymidylate
  and purine
• nucleotides ( DNA).
• Mechanisms MTX competes with FA for the active
  site
• of dihydrofolate reductase (DHFR) and thymidylate
  
• synthetase (TS). By blocking this step, MTX
  prevents
• nucleic acid synthesis and causes cell death.

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24-h IV infusion of HDMTX
Prognosis Css pl, CLtotMTX Toxicity high-risk
CssMTX end co-variates AUCMTX ,
low urine pH, emesis
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target Css for malignant cells
1
infusion

• Toxicity
• high risk Css pl
• iniciation and continuation
• of LV rescue

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Estimation of an individualized dose based on
CL estimates using 1and 6hCpl (Wall 2000, Evans,
Relling 1994,1998)
leucovorin
MTX
critical plasma concentration
for normal cells
critical duration of exposure of normal cells
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Pharmacokinetics MTX is reasonably absorbed when
administered by mouth in low dosage. (When doses
exceed 30 mg, progressively less of the drug is
absorbed) Metabolic transformation ?
intracellularly in the form of polyglutamates
(n1-7) MTX selectivity (cells capable of
this conversion e.g. lymphoblasts may be
expected to be more susceptible to cell
kill by this drug). ? in the liver the
significant amount of the drug (7-30) is
metabolized by hydroxylation at the 7 position
(7-OH MTX). MTX is excreted primarily
unchanged by the kidney.Thus patients with renal
impairment should not be treated with MTX
because of the prolonged blood levels that may
lead to increased hematological and
gastrointestinal toxicity.
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Dosage MTX is used in several different
regimens ? low dose (LDMTX) up to 50 mg/m2/week
antiinflammatory and immunosuppresive
action (psoriasis) orally, s.c. ? intermediate
dose lt 1 g/m2 (malignancy) IV ? high dose
(HDMTX) gt 1 g/m2 (malignancy)
IV Intrathecal administration is needed to
prevent relapse due to malignant cells hidden
after biological barriers ( blood-brain barrier,
testes, eyes).
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Antagonist folinic acid (leucovorin)- rescue
Adverse effects and toxicity nauzea and
vomiting, diarrhea stomatitis myelosuppresion rena
l dysfunction seizures (especially after
intrathecal administration). Less common toxic
effects are skin rash, pleuritis and hepatitis.
Acute renal failure can be caused by
tubular obstruction by crystals of MTX. ?
Diuresis (gt 3 l/day) with alkalinization of the
urine (pH 7-7.5 ) by IV administration of sodium
bicarbonate reduces the incidence of
nephrotoxicity.
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Usage LDMTX is indicated in severe psoriasis
(immunosuppressant), asthma, rheumatic
polyarthritis, and maintaining treatment of
acute lymphoblastic leukemia (ALL). This
treatment does not require folinic acid
rescue. Intermediate and particularly HDMTX are
used in malignancy. HDMTX in the inicial phase
of ALL protocol, lymphomas and some solid tumors
including osteogenic sarcoma.
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b. P y r i m i d i n e antagonists 5 -
fluorouracil ? active metabolite of 5-FU that
inhibits DNA synthesis through potent
inhibition of thymidylate synthase is
5-fluorodeoxyuridin MP (5-FdUMP) ?
modulation of 5-FU action FdUMP forms the
ternary complex with an excess folate
coenzyme and thymidylate synthase. For this
reason a stable folate precurzor leucovorin is
used followed by 5-FU treatment (colon
cancer). Pharmacokinetics 5-FU is absorbed
erratically after oral administration and,
therefore, is administered IV.
Toxicity leukopenia and thrombocytopenia, GIT
toxicity. Stomatitis and diarrhea usually occurs
4-7 days after treatment.
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Therapeutic uses several solid tumors, most
notably colon cancer, breast cancer, and head
and neck cancers. 5-FU is metabolized in the
liver. Then this drug can be administered also
into the hepatic artery. This method achieves
high local concentrations, with decreased
systemic toxicity and is used to treat isolated
hepatic metastases from colon cancer.
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Cytosine arabinoside (ara-C) is an analog of
deoxycytidine ? inhibits DNA polymerase or is
incorporated into DNA. ? is used IV as a
pulze dose or a continuous infusion. Toxicity
myelosuppresion, neurological, GIT and liver
toxicity (the dose-related) Usage the drug of
choice for the treatment of acute myelocytic
leukemia (AML).
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c. Purine antagonists. 6-mercaptopurine (6-MP)
and 6-thioquanine
(6-TG) are converted to nucleotides
intracellularly and block synthesis of purines.
They are administered orally and used
in the treatment of ALL. Azathioprine is
a prodrug giving 6-MP (a potent immunsupressive
agent).
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Metabolická konverze 6-merkaptopurinu
methylmercaptopurine
methylthioinosine-
e
monophosphate
TPMT
TPMT

nucleotide
nucleotide
6-mercaptopurine
mercaptopurine
thioguanine
HPRT


(thioinosine-
(thioguanosine
monophosphate)
monophosphate
thioxantosine
monophosphate
XO


inhibition


DNA
thioxantine
thiourine acid
bioactivation
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3. PLANT ALKALOIDS Podophyllotoxins Vinca
alkaloids- Paclitaxel Podophyllotoxins (from
mandrake or May apple) - etoposide increases
degradation of DNA (similar to that seen after
irradiation), possibly via stabilisating the DNA-
topoisomerase II complex. It is administered IV
or orally. Etoposide is very active in
leukemias, testicular cancer, lymphomas and
Hodgkins disease. Indications hematological
neoplasms (leukemias, lymphomas).
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• Vinca alkaloids- vinblastine and vincristine
• bind to tubulin, a protein that forms the
  microtubules
• that are essential for the formation of the
  spindle
• that separates the chromosomes during mitosis-
• "spindle poisons".
• ? low oral bioavailability (given IV).
• Toxicity
• Vinblastine leukopenia.
• Vincristine neurotoxicity
• paresthesia of the fingers
• and lower extremities -
• profound weakness of motor strenght
• (of dorsiflexing the foot and extensors of the
  wrists) -
• obstipation and paralytic ileus

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Usage vinblastine - treatment of testicular
cancer and Hodgkins
disease vincristine - breast cancer, lymphomas,
acute lymphoblastic
leukemia
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Paclitaxel is spindle poison This drug is
most useful in ovarian cancer and in advanced
breast cancer.
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4. ANTIBIOTICS Anthracyclines doxorubicin,
daunorubicin. There are three main mechanisms of
action ? intercalation between adjacent base
pairs in DNA, thus inhibiting further
nucleic acid synthesis and leading to
fragmentation of DNA and inhibition of DNA
repair. ? membrane binding alters membrane
function. This alters sodium and calcium
concentrations seen in myocardium and could
be involved in the development of
cardiomyopathy. ? free radical formation (
cardiotoxicity).
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Toxicity Cardiotoxicity acute and chronic A c u
t e toxicity shortly after administration with
the develop- ment of various arrhythmias, that
are occasionally life-threatening. Ch r o n i c
toxicity Cardiomyopathy occurs leading to death
in up to 60 of those who develop signs of
congestive cardiac failure. The role of
dexrazoxane. Bone marrow suppression Alopecia Extr
avasation causing severe tissue
necrosis. Doxorubicin and daunorubicin are given
IV. Vd of doxorubicin is very large. Its
hepatic extraction is high with 40 appearing in
bile. Dose reduction is recommended in liver
disease. Daunorubicin penetrates tissues less
effectively. Indications
acute leukemia, lymphomas, sarcomas and a wide
range of carcinomas.
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Bleomycin is a mixture of several polypeptide
antibiotics It prevents thymidine incorporation
into DNA. Adverse effects
transient fever mouth ulceration in high
doses pulmonary diffuse interstitial fibrosis
which can be fatal. Alopecia This antibiotic is
given IV or i.m Bleomycin is used in lymphomas,
testicular carcinoma, and various squamous cell
carcinomas
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5. HORMONES and antagonists H. can cause
remission in certain types of cancer (breast and
prostate). Ways in which hormones can affect
malignant cells ? a direct cytotoxic action on
the malignant cells. This is likely if cancer
cells that are normally dependent on a specific
hormone are exposed to a high concentration of a
hormone with the opposite effect (if a carcinoma
arises from cells of the prostate that are
testosterone dependent, .estrogens in large
doses are cytotoxic to the cancer) ? a hormone
may suppress production of the hormones by a
feedback mechanism. S e x h o r m o n e
s Estrogens are used in the management of
prostatic and breast
carcinoma
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Progestogens megesteron, medroxy-progesteron
acetate adenocarcinoma of the body of the
uterus and in advanced breast cancer, carcinoma
of the kidney. G l u c o c o r t i c o s t e r
o i d s are cytotoxic to lymphoid cells and are
used with combination with other cytotoxic
agents in treating lymphomas, myeloma and to
induce a remission in acute lymphoblastic
leukemia.
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• H o r m o n e a n t a g o n i s t s
• Anti-estrogens
• tamoxifen - in breast tissue
• competes with endogenous estrogens for
• the estrogen receptors and inhibits the
  transcription of
• estrogen-responsive genes.
• T. is remarkably effective in some cases of
• hormone-dependent breast cancer
• Anti-androgens
• flutamide is used in prostate tumors
• Adrenal hormone synthesis inhibitors inhibit
• sex hormone synthesis. Aminoglutethimide.

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Aminoglutethimide ? inhibits adrenal synthesis
of estrogens, glucocorticoids and
mineralocorticoids by inhibition of the
enzyme producing their common precursor-
pregnandione ? inhibits tissue aromatase
blocking conversion of androgens to
estrogens. Ovarian aromatase is resistant to
this inhibition, so aminoglutethimide is
only useful in postmenopausal women.
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Pharmacokinetics polymorphic acetylation to an
inactive N-acetyl metabolite. Fast acetylators -
slow acetylators. Adverse effects dizziness,
lethargy are common on starting treatment but
decline during chronic dosing (probably due to
enzyme induction). Usage A. is effective in
about 30 of postmenopausal patients with best
effects on skin and breast disease. The response
of bone metastases is also good.


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6. PLATINUM COMPOUNDS Cisplatin
(cis-diaminedichlorplatinum) is an inorganic
platinum complex. ? mechanism of action DNA
synthesis by formation of intra-and interstrand
cross-links with DNA molecule. Adverse effects,
toxicity ? severe vomiting ? nephrotoxicity is
dose-related (acute distal tubular
necrosis). Prevention the patients is fully
hydrated by IV infusion combined with manitol and
furosemide. ? hypomagnesemia ? ototoxicity
develops in up to 30.
Peripheral neuropathy can be disabling. ?
myelosuppression
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Cisplatin is the most effective single agent in
testicular teratomas, but is usually given in
combination with other cytotoxic drugs. C. has
been used with some succes in head and neck and
bladder cancers -IV . Carboplatin is less
toxic (renal toxicity or ototoxicity),
neuropathy is rare and vomiting although common,
is less severe than after cisplatin. Oxaliplatin

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7. M I S C E L L A N E O U S AGENTS Procarbazine
depresses DNA synthesis. Its main use is in
treating Hodgkins disease. 8. I N T E R F E R
O N S hairy cell leukemia, lowgrade non-Hodgkins
lymphoma, chronic myeloid leukemia.
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