Cancer Chemotherapeutics

Cancer Chemotherapeutics
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TABLE OF CONTENTS
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ALKYLATING AND OXIDIZING AGENTS

ANTIMETABOLITES

ANTIBIOTICS

MITOTIC INHIBITORS

CHROMATIN FUNCTION INHIBITORS

HORMONES AND HORMONE INHIBITORS

ANTIBODIES

IMMUNOMODULATORS

ANGIOGENESIS INHIBITORS

MISCELLANEOUS

RESCUE/PROTECTIVE AGENTS

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ALKYLATING AND OXIDIZING AGENTS

I. NITROGEN MUSTARDS
- mechlorethamine (Mustargen)
- cyclophosphamide (Cytoxan, Neosar)
- ifosfamide (Ifex)
- phenylalanine mustard; melphalen (Alkeran)
- chlorambucol (Leukeran)
- uracil mustard
- estramustine (Emcyt)
II. ETHYLENIMINES
- thiotepa (Thioplex)
III. ALKYL SULFONATES
- busulfan (Myerlan)
IV. NITROSUREAS
- lomustine (CeeNU)
- carmustine (BiCNU, BCNU)
- streptozocin (Zanosar)
V. TRIAZENES
- dacarbazine (DTIC-Dome)
- temozolamide (Temodar)
VI. PLATINUM COORDINATION COMPLEXES
- cis-platinum, cisplatin (Platinol, Platinol AQ)
- carboplatin (Paraplatin)
VII. OTHERS
- altretamine (Hexalen)
- arsenic (Trisenox)

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ANTIMETABOLITES

I. FOLIC ACID ANALOGS
- methotrexate (Amethopterin, Folex, Mexate, Rheumatrex)
II. PYRIMIDINE ANALOGS
- 5-fluoruracil (Adrucil, Efudex, Fluoroplex)
- floxuridine, 5-fluorodeoxyuridine (FUDR)
- capecitabine (Xeloda)
- fludarabine: (Fludara)
- cytosine arabinoside (Cytaribine, Cytosar, ARA-C)
II. PURINE ANALOGS
- 6-mercaptopurine (Purinethol)
- 6-thioguanine (Thioguanine)
- gemcitabine (Gemzar)
- cladribine (Leustatin)
- deoxycoformycin; pentostatin (Nipent)

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ANTIBIOTICS

doxorubicin (Adriamycin, Rubex, Doxil, Daunoxome- liposomal preparation)
daunorubicin (Daunomycin, Cerubidine)
idarubicin (Idamycin)
valrubicin (Valstar)
epirubicin
mitoxantrone (Novantrone)
dactinomycin (Actinomycin D, Cosmegen)
mithramycin, plicamycin (Mithracin)
mitomycin C (Mutamycin)
bleomycin (Blenoxane)
procarbazine (Matulane)

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MITOTIC INHIBITORS

I. TAXANES (DITERPENES)
- paclitaxel (Taxol)
- docetaxel (Taxotere)
II. VINCA ALKALOIDS
- vinblatine sulfate (Velban, Velsar, VLB)
- vincristine sulfate (Oncovin, Vincasar PFS, Vincrex)
- vinorelbine sulfate (Navelbine)

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CHROMATIN FUNCTION INHIBITORS

I. CAMPTOTHECINS
- topotecan (Camptosar)
- irinotecan (Hycamtin)
II. EPIPODOPHYLLOTOXINS
- etoposide (VP-16, VePesid, Toposar)
- teniposide (VM-26, Vumon)

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HORMONES AND HORMONE INHIBITORS

I. ESTROGENS
- diethylstilbesterol (Stilbesterol, Stilphostrol)
- estradiol, estrogen (many brands)
- esterified estrogens (Estratab, Menest)
- estramustine (Emcyt)
II. ANTIESTROGENS
- tamoxifen (Nolvadex)
- toremifene (Fareston)
III. AROMATASE INHIBITORS
- anastrozole (Arimidex)
- letrozole (Femara)
IV. PROGESTINS
- 17-OH-progesterone (many brands)
- medroxyprogesterone (many brands)
- megestrol acetate (Megace)
V. GnRH AGONISTS
- goserelin (Zoladex)
- leuprolide (Leupron)
VI. ANDROGENS
- testosterone (many brands)
- methyltestosterone (many brands)
- fluoxmesterone (Android-F, Halotestin)
VII. ANTIANDROGENS
- flutamide (Eulexin)
- bicalutamide (Casodex)
- nilutamide (Nilandron)
VIII. INHIBITORS OF SYNTHESIS
- aminoglutethimide (Cytadren)
- ketoconazole (Nizoral)

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ANTIBODIES

rituximab (Rituxan)
trastuzumab (Herceptin)
gemtuzumab ozogamicin (Mylotarg)
tositumomab (Bexxar)
bevacizumab

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IMMUNOMODULATORS

denileukin diftitox (Ontak)
levamisole (Ergamisol)
bacillus Calmette-Guerin, BCG (TheraCys, TICE BCG)
interferon alpha-2a, alpha 2b (Roferon-A, Intron A)
interleukin-2, aldesleukin (ProLeukin)

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ANGIOGENESIS INHIBITORS

thalidomide (Thalomid)
angiostatin
endostatin

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MISCELLANEOUS

imatinib mesylate; STI-571 (Gleevec)
l-aspariginase (Elspar, Kidrolase)
pegaspasgase (Oncaspar)
hydroxyurea (Hydrea, Doxia)
leucovorin (Wellcovorin)
mitotane (Lysodren)
porfimer (Photofrin)
tretinoin (Veasnoid)

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RESCUE/PROTECTIVE AGENTS

dexrazoxane (Zinecard)
amifostine (Ethyol)
G-CSF (Neupogen)
GM-CSF (Leukine)
Erythopoetin (Epogen, Procrit)
Oprelvekin; IL-11 (Neumega)

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MECHANISM OF ACTION
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ALKYLATING AND OXIDIZING AGENTS

cell cycle non-specific (greater effect in G1,S)
alkylation of DNA (through carbonimum ion intermediates); radiomimetic
covalent cross-linking of DNA, RNA and proteins
single-strand DNA breaks
abnormal DNA base-pairing

I. NITROGEN MUSTARDS
- mechlorethamine: alkylation of G(N7)
- cyclophosphamide: alkylation by hydroxylated metabolites. Also acts as an immuno-supressant
- ifosfamide: activated by liver enzymes
- phenylalanine mustard: cross-links DNA and RNA
- chlorambucol: cross-links DNA and RNA
- uracil mustard
- estramustine: facilitated by ER mediated uptake
II. ETHYLENIMINES
- thiotepa: cross-links DNA and RNA.
III. ALKYL SULFONATES
- busulfan: cross-links DNA and RNA.
IV. NITROSUREAS
- converted into a carbonium ion (alkylating agent) and isothiocyanate molecule (may interact with proteins)
- more active in dividing cells
- lomustine
- carmustine
- streptozocin
V. TRIAZENES
- dacarbazine: alkylation; purine anti-metabolite; binds to protein sulfhydryl groups
- temozolamide: converted to active form (MTIC) at neutral pH, causing alkylation/methylation of guanine (O6 and N7)
VI. PLATINUM COORDINATION COMPLEXES
- cross links DNA strands; affinity for alkylation at G(N7) and A(N7)
- interstrand and intrastrand cross-linking; binds to protein SH groups
- cis-platinum
- carboplatin
VII. OTHERS
- altretamine: active liver metabolites. exact mechanism unknown
- arsenic: induces free radical chain reactions. used in acute promyelocytic leukemia

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ANTIMETABOLITES

S phase specific
structurally related to normal cellular components
interfere with nucleotide synthesis
compete with cellular nucleotides in DNA and RNA synthesis
I. FOLIC ACID ANALOGS
- methotrexate: blocks folate reductase, and thus intereferes with transfer of one-carbon units, thereby inhibiting production of methionine, A, G, T.
II. PYRIMIDINE ANALOGS
- 5-fluoruracil: converted to 5-Fd(UMP) inhibits dUMP -> TMP conversion via binding to thymidylate synthetase
- floxuridine, 5-fluorodeoxyuridine: prodrug of 5-FU; hydrolysis by thymidine phosphorylase to 5-FU
- capecitabine: prodrug of 5-FU; hepatic metabolism to 5'-deoxy-5-fluorocytidine which is converted to 5'-deoxy-5-fluorouridine by cytidine deaminase; hydrolysis by thymidine phosphorylase to 5-FU
- fludarabine: has modifications in both the base and sugar moieties; activated by phosphorylation; incorporates into DNA, inhibiting DNA polymerization, terminating chain elongation; inhibits DNA proof-reading exonuclease activity
- cytosine arabinoside: analog of dC, with D-arabinose sugar group; activated by phosphorylation; antagonizes d(CTP), inhibiting DNA polymerase; incorpoarted into DNA -> inhibition of DNA chain elongation and SS breaks; inhibits CDP -> dCDP
III. PURINE ANALOGS
- 6-mercaptopurine: analog of hopoxanthine; intracellular activation; competitive inhibitor of purine synthesis
- 6-thioguanine: intracellular activation; competitive inhibitor of purine synthesis
- gemcitabine: competes with dCTP for incorporation into DNA; masked from DNA repair enzymes; inhibits DNA synthesis
- cladribine: phosphorylated by deoxycytidine kinase; metabolite impairs synthesis of new DNA, inhibits repair of existing DNA, disrupts cellular metabolism
- pentostatin: inhibits adenosine deaminase, increasing intracellular dATP

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ANTIBIOTICS

cell cycle non-specific, except:
- intercalation into double-stranded DNA and disruption of DNA; binding to DNA helix
- agents inhibit DNA synthesis, nucleotide incorporation, DNA dependent RNA synthesis, DNA uncoiling and/or topoisomerase II (leading to strand breaks).
  - doxorubicin: intercalates in DNA, binding to S-P backbone; binds to cell membranses, blocking phosphatidyl-inositol activation; free radical mediated DNA single-strand breaks: reduced semiquinone free radical metabolites (via P450) -> reduced O2 -> superoxide and H2O2; also inhibits topoisomerase II
  - daunorubicin: same mechansism as doxorubicin
  - idarubicin: same mechansism as doxorubicin
  - valrubicin: metabolites are active; less tight DNA binding; tends to arrest cells in G2; also inhibits topoisomerase II
  - epirubicin: same mechansism as doxorubicin
  - dactinomycin: intercalates in small groove of helix and binds to dG; tight binding of the dactinomycin prevents unwinding of the DNA; also inhibits topoisomerase II
  - mithramycin: intercalates into to DNA; binds to surface of DNA helix. also used for hyperCa++
  - mitomycin C: activated metabolite cross links DNA (and RNA)
  - mitoxantrone: high-affinity intercalation; cells late in S phase more sensitive
  - bleomycin: Cu and Fe chelating glycopeptides; cause DNA stand breaks via oxidative processes (mediated by superoxide and H2O2); cleaved at G-C and G-T sequences; inhibits DNA ligase and DNA synthesis (RNA and protein synthesis are less affected).
  - procarbazine: directly damages DNA; depolymerizes DNA; inhibits DNA, RNA and protein synthesis
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MITOTIC INHIBITORS
- cell cycle specific (M phase)
- disrupts the mitotic spindle, inhibiting chromosomal segregation and thereby blocking mitosis
- I. TAXANES (DITERPENES)
  - derived from bark of Pacific Yew
  - prevents microtubular depolymerization thereby inhibiting reorganization of the microtubular network
  - microtubular stabilization also promotes the formation of abnormal bundles of microtubules
  - paclitaxel
  - docetaxel
- II. VINCA ALKALOIDS
  - derived from the Madagascar periwinkle plant
  - binds to tubulin causing termination of microtubular assembly, arresting cells in metaphase
  - formation of paracrystalline aggregates of vinca:tubulin shifts the equilibrium further toward microtubule disassembly
  - inhibits DNA dependent RNA synthesis, purine synthesis and amino acid metabolism
  - vinblatine sulfate
  - vincristine sulfate
  - vinorelbine sulfate
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CHROMATIN FUNCTION INHIBITORS
- I. CAMPTOTHECINS
  - derived from the bark of Camptotheca acuminata
  - cell cycle specific (S phase)
  - binds to topoisomerase I-DNA complex, preventing religation of breaks
  - induces reversible single-strand breaks, relieving torsional strain of DNA
  - double strand breaks formed during DNA synthesis
  - topotecan
  - irinotecan
- II. EPIPODOPHYLLOTOXINS
  - derived podophyllotoxin, which arise from the Mayapple root
  - cell cycle specific (S-G2 phase); arrests cells in metaphase
  - complexes with topoisomerase II, inhibiting its enzymatic function.
  - topoisomerase is needed to unwind DNA and allow transcription and replication
  - drug-enzyme complex also causes production of DNA double stranded breaks and DNA-protein cross linkages
  - possibly inhibits nucleotide transport
  - etoposide
  - teniposide
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HORMONES AND HORMONE INHIBITORS
- I. ESTROGENS
  - binds to estradiol hormone receptors, inhibitng tumor growth in estrogen sensitive tumors
  - diethylstilbesterol
  - estradiol, estrogen
  - esterified estrogens
  - estramustine: see alkylating agents above
- II. ANTIESTROGENS
  - blocks estradiol hormone receptors, possibly inhibitng DNA synthesis and thus tumor growth in estrogen sensitive tumors
  - tamoxifen
  - toremifene
- III. AROMATASE INHIBITORS
  - inhbits aromatase (primarily in fatty tissue) which converts adrenal hormones into estrogen
  - decreased serum estrogen levels inhibit tumor growth in estrogen sensitive tumors
  - anastrozole
  - letrozole
- IV. PROGESTINS
  - blocks progesterone hormone receptors, inhibitng tumor growth by unknown mechanism
  - 17-OH-progesterone
  - medroxyprogesterone
  - megestrol acetate
- V. GnRH AGONISTS
  - synthetic analog of luteinizing hormone-releasing hormone
  - overstimulation of of the LHRH-gonadotropin axis leads to inhibition of gonadotropin release, thereby diminishing estrogen and androgen formation
  - hormone sensitive tumors are therefore inhibited
  - goserelin
  - leuprolide
- VI. ANDROGENS
  - binds to androgen hormone receptors, inhibitng tumor growth via an anti-estrogenic effect in estrogen sensitive tumors
  - testosteraone
  - methyltestosterone
  - fluoxmesterone
- VII. ANTIANDROGENS
  - binds to androgen hormone receptors, inhibiting androgen uptake and thus inhibitng tumor growth in androgen sensitive tumors
  - flutamide
  - bicalutamide
  - nilutamide
- VIII. INHIBITORS OF SYNTHESIS
  - aminoglutethimide: interferes with adrenal steroid hormone synthesis; specically inhibits conversion of cholesterol to delta-5-pregnenolone (inhibiting corticosteroids, androgens, estrogens)
  - ketoconazole: interferes with adrenal steroid hormone synthesis
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ANTIBODIES
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IMMUNOMODULATORS
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ANGIOGENESIS INHIBITORS
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MISCELLANEOUS
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RESCUE/PROTECTIVE AGENTS
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by Michael T. Milano, MD PhD
MTMilano@yahoo.com
www.geocities.com/MTMilano/palm/