Vous êtes sur la page 1sur 6

CHEMOTHERAPEUTIC FAMILIES

CLASS DRUGS GENERAL MECHANISM OFACTION

ALKYLATING AGENTS Nitrogen Mustards Cyclophosphamide and itosfamide  Cytotoxicity due to covalent bonding with various cell
Melphalan (L-sarcolysin) constituents
Chlorambucil  Do not discriminate between cycling and non-cycling
Mechlorethamine cells
Ethylenimines & Methylmelamines Hexamethylmelamine  Most toxic for rapidly dividing cells
Thiotepa  Also mutagenic and carcinogenic and can lead to
Alkylsulfonates Busulfan secondary carcinoma like leukemia
Nitrosoureas Carmustine (BCNU)
Lomustine (CCNU)
Semustine (methyl CCNU)
Streptozocin (streptozotocin)
Triazenes Dacarbazine
ANTIMETABOLITES Folic Acid Analog Methotrexate (amethopterin)  Structurally related to normal cellular components
Pyrimidine Analogs 5-Fluorouracil (5-FU, fluorouracil)  Inhibit synthesis of purine or pyrimidine nucleotides or
Floxuridine (FUdR) compete with them during DNA or RNA synthesis
Cytarabine (cytosine arabinoside)  Maximal cytotoxic effects are S phase-specific
Purine Analogs and Related 6-mercaptopurine (mercaptopurine)
Inhibitors Thioguanine (6-thioguanine)
Pentostatin
NATURAL PRODUCTS Antibiotic Dactinomycin  Topoisomerase interactive agents
Epipodophyllotoxins Etoposide
Teniposide
Anthracenedione Mitoxantrone
Anthracycline Antibiotics Daunorubicin (daunomycin, rubidomycin)  Inhibit DNA and RNA synthesis
Doxorubicin  Effects on topoisomerase II
Idarubicin
Epirubicin

4
CLASS DRUGS GENERAL MECHANISM OFACTION

NATURAL PRODUCTS (cont) Glycopeptide Antibiotic Bleomycin Fragmentation of DNA chain with release of free bases
Vinca Alkaloids Vinblastine Antimicrotubule agents
Vincristine
Taxanes Paclitaxel
Enzymes L-asparaginase Breaks down asparagine to aspartic acid and
ammonia
Biological Response Modifier Interferon-alpha
HORMONES AND Adrenocorticosteroids Prednisone Inhibition of lymphocyte proliferation
ANTAGONISTS Progestins Medroxyprogesterone acetate For hormone-sensitive tumors
Hydroxyprogesterone caproate
Megestrol acetate
Estrogens Diethylstilbestrol
ethinylestradiol
Antiestrogen Tamoxifen
Antiandrogen Flutamide
GRH Analog Leuprolide
MISCELLANEOUS AGENTS Platinum Family Cisplatin Intrastrand cross-linking and denaturation of DNA
Carboplatin
Substituted Urea Hydroxyurea Inhibits ribonucleotide reductase
Methylhydrazine Derivatives Procarbazine  Inhibits DNA & RNA synthesis
 Interferes with mitosis at interphase
Adrenocortical Suppressant Aminoglutethimide  Aromatase inhibitor
Radiation and Chemotherapy Leucovorin  Bypass of inhibited DHF reductase (by methotrexate)
Protector

5
ALKYLATING AGENTS
CLASSIFICATION DRUG MECHANISM OF ACTION OTHER FEATURES ADVERSE EFFECTS
NITROGEN MUSTARDS Cyclophosphamide  Inactive until metabolized in the liver by cytP450  Most commonly used alkylating agent  Nausea and vomiting
Itosfamide  Cytotoxicity due to reaction of DNA with phosphoramide  Used as immunosuppressant  Bone marrow depression
mustard  Usually given orally or IV but may be  Hemorrhagic cystitis
given IM or into the pleural and peritoneal  Due to acrolein liberated
cavities
during hydroxylation
 Ameliorated by increased fluid
intake and administration of
sulfhydryl donors
Melphalan Similar to that of other nitrogen mustards  Incomplete absorption Mainly hematologic
 May be given orally
Mechlorethamine  Transported into the cell by a choline uptake process  Very unstable  solutions made just prior  Severe nausea and vomiting
 Loss of chloride ion forming a reactive intermediate  to administration (central)
alkylation of guanine bases (N7)  cross-linking between  Powerful vesicant (blistering agent)  Severe bone marrow depression
guanine residues, depurination  DNA strand breakage  Administered IV only (cause severe  Severe tissue damage with
tissue damage if extravasation occurs) extravasation
Chlorambucil Similar to that of other agents  Oral absorption adequate May be given for months or years
 Slowest acting of All of the above without producing myelosuppression
statements are correct. the nitrogen
mustards
ETHYLENIMINES AND Thiotepa Formation of DNA cross-links  Rapidly metabolized to TEPA Myelosuppression
METHYLMELAMINES  Only 10% appears in the urine;
remainder rapidly metabolized; interacts
with biological molecules or undergoes
spontaneous degradation
Hexamethylmelamine Requires microsomal activation to exhibit cytotoxicity Structurally similar to thiotepa
AKLYSUFONATES Busulfan  Depresses formation of granulocytes and platelets in low No effect or lymphoid tissue or the GIT Thrombocytopenia
dosage
 Depresses red cell formation in high doses
NITROSOUREAS Carmustine  Cross-;linking of strands of DNA to inhibit DNA replication   Non-dividing cells can escape cell death  Delayed hematopoietic depression
Lomustine affects RNA and protein synthesis if DNA repair occurs  Renal toxicity
 Liberate organic isocyanates which interact with lysine  Carmustine is given IV while lomustine is  Pulmonary fibrosis
residues in proteins  inactivate DNA repair enzymes given orally
 They alkylate DNA in resting cells but is only expressed  Lipophilic and can cross BBB
during cell division  Undergo extensive metabolism
 Excreted in the kidney
Streptozocin Specifically toxic to beta cells of the islets of Langerhans  For treatment of insulinomas Reversible renal damage
 Diabetogenic
Dacarbazine Activated by N-methylation in the liver  cleaved in target cell   Given parenterally  Myelotoxicity
release of alkylating agent  Severe nausea and vomiting

6
ANTIMETABOLITES

CLASSIFICATION DRUG MECHANISM OF ACTION OTHER FEATURES ADVERSE EFFECTS


FOLIC ACID ANALOGS Methotrexate  Inhibits dihydrofolate reductase  depletes intracellular  Higher affinity for the enzyme than DHF  Myelosuppression
tetrahydrofolate  affects thymidilate synthesis  Usually given orally  Damage to GIT epithelium
 Nephrotoxicity in high doses
PYRIMIDINE ANALOGS Fluorouracil (5-FU) Converted to FDUMP (“fraudulent molecule)  interacts with  May be given orally or IV  GIT epithelial damage
thymidilate synthetase and cofactors  no thymidilate   Readily crosses BBB  Myelotoxicity
inhibition of DNA synthesis  Rapidly undergoes conversion to  Cerebellar disturbances may
nucleotide in the liver occur
 20% excreted unchanged in the urine
Cytarabine  Enters target cell and undergoes the same phosphorylation  Given IV or SC  Potent myelosuppression
reaction as the physiological nucleoside (2’ deoxycytidine) to  Metabolized by the liver  GIT damage
its triphosphate  Crosses BBB to a limited extent
 Inhibition of DNA polymerase by the triphosphate  inhibit
DNA synthesis
 Inhibition of repair synthesis
PURINE ANALOGS 6-mercaptopurine Converted to fraudulent molecules (6-thioIMP and 6-thioGMP)   Well-absorbed when given orally  Bone marrow depression
can be incorporation into RNA; inhibit de novo purine  Undergoes first-pass metabolism  GIT epithelial damage
biosynthesis  Liver damage, rarely
Thioguanine  Given orally Myelosuppression
Azathioprine Converted to mercaptopurine in vivo
Pentostatin  Inhibits adenosine deaminase  no inosine (from adenosine)
 interfere with purine metabolism

7
NATURAL PRODUCTS

CLASS DRUG SOURCE MECHANISM OF ACTION OTHER FEATURES ADVERSE EFFECTS


ANTIBIOTICS Crystalline Dactinomycin Streptomyces  Binds with double helical DNA  block  Has effects on all phases of  Anorexia
(Actinomycin D) DNA transcription by RNA polymerase the cell cycle, but morepotent on rapidly  Nausea and vomiting
 May have similar action as proliferating cells  Myelosuppression
anthracyclines on topoisomerase II  Usually given parenterally  Severe injury with extravasation
 Does not cross BBB
Antracycline Daunorubicin Streptomyces  Intercalation with DNA  stabilize  Idarubicin structurally related to  Binds with double helical DNA 
Doxorubicin peucetius (“freeze”) the DNA-topoisomerase doxorubicin block DNA transcription by RNA
Idearubicin complex  single and double strand  Administered IV polymerase
breaks occur  Rapidly taken up by tissues but do not May have similar action as
 React with cyt P450 reductase  cross BBB anthracyclines on topoisomerase
produce superoxide radicals  Excreted mainly in the bile
 Intramolecular electron transfers 
generation of free radicals
 React with cell membranes  alter
function
Glycopeptide Bleomycin Streptomyces Degrade preformed DNA  chain  Water-soluble  Little myelosuppression
verticilius fragmentation  release of free bases  Administered parenterally or instilled  Pulmonary toxicity
(fermentation directly into the bladder  Nausea and vomiting
products)  Hyperthermia
 Acute, fulminant reaction in patients
with lymphoma
Others Plicamycin Streptomyces Intercalates with DNA similar to  Administered IV  Toxic to bone marrow, liver and
(mithramycin) plicatus dactinomycin, with preference for GC  Severely toxic kidneys
pairs  Severe hemorrhagic diathesis in 5-
10%
Mitomycin Streptomyces  Intracellular enzymatic or spontaneous  Given IV  Potent radiosensitizer
(mtomycin C) caespitosus reduction  bifunctional or  Widely distributed but is not detected in  Myelosuppression
trifunctional alkylating agent  inhibits the brain  Interstitial fibrosis in the lungs
DNA cross-linking and synthesis  Used primarily in combination with 5-FU,
 Single strand breakage of DNA cisplatin and doxorubicin
 Chromosomal breaks

8
CLASS DRUG SOURCE MECHANISM OF ACTION OTHER FEATURES ADVERSE EFFECTS
PLANT Vinca alkaloids Vincristine Periwinkle Bind to tubulin  inhibit polymerization  Given parenterally and  Relatively non-toxic
DERIVATIVES Vinblastine into microtubules  no spindle formation extravasation causes tissue  Vincristine neurotoxic (paresthesia,
Vindesine  arrest of mitosis at metaphase damage muscular abnormalities)
 Rapidly sequestered into  Vinblastine causes leukopenia
the cells  Vindesine moderately neurotoxic and
 Excreted primarily in the myelotoxic
bile
Epipodophyllotoxin Etoposide Mandrake  May be due to inhibition of  May be given orally or IV  Nausea and vomiting
Teniposide root mitochondrial function and of  Widely distributed  Myelosuppression
nucleoside transport  Does not cross BBB  Hair loss
 Effect on topoisomerase II  Excreted mainly in the urine
Taxanes Paclitaxel Yew tree Stabilizes (freezes) microtubules in Given as infusion over 3 to 24 hours  Bone marrow suppression
(taxol) bark polymerized state  Mucositis
ANTHRACENEDIONE Mitoxantrone  Causes strand breaks in DNA  Structural analog of doxorubicin  Less cardiotoxic, myelosuppressive
(mediated by topoisomerase)  Administered IV than doxorubicin
 Intercalates with DNA

ENZYMES L-asparaginase  Breaks down asparagine to ammonia  Given parenterally  Minimal bone marrow and GIT
and aspartic acid  deprive cells of toxicity
asparagines  no protein synthesis   May cause ammonia toxicity
cell death
 Produces cell death through activation
of apoptosis