Professional Documents
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Cancer Chemotherapy
Cancer Chemotherapy
Cancer Chemotherapy
DRUGS
Principles of Cancer
Chemotherapy
ONCOLOGY
Epidemiology OVERVIEW
Leading causes of death
• Alkylating agents
• Antimetabolites
• Antibiotics
• Natural products
• Hormonal agents
• Miscellaneous
Cell Cycle Specificity of Anticancer
drugs
• cycle/phase non-specific
alkylating agents
• phase specific
• G1 phase(RNA synthesis) • G2 phase(RNA,
L-asparaginase protein synthesis)
steroids bleomycin
• S phase(DNA,RNA, topo I inhibitors
• Impt targets
• G N7 – strongly nucleophilic
• DNA becomes cross-linked w/ agent
• Intra- or inter-strand
• Decr’d transcr’n, repl’n
• Chain scission, so strand breaks
• Inappropriate base pairing (alkylated G w/ T)
ALKYLATING AGENTS
• Mechlorethamine
• Melphalan
• Cyclophosphamide
• Chlorambucil
• Ifosfamide
(MCI)
MECHLORETHAMINE(MUSTINE)
MOA:
• In aqueous sol. It loses a chloride atom and forms a cyclic
ethylenimonium ion. This carbonium ion then interacts
with nucleophilic groups (N7 and O6) of guanine, and leads
to an inter-strand cross-linking of DNA
MOA:
• similarly results in the cross-linkages of DNA due to the
chloroethyl moieties with adjacent nucleotide bases
• Prodrug- metabolized in the liver by CYP450 enzymes to
phosphoramide and acrolein
DRUG NOTES t1/2 Elimn
IFOSFAMIDE O
Cl
Ifosfamide - Ifex®
• Analogue of cyclophosphamide
• Prodrug: requires CYP450 for activation to 4-
hydroxyifosfamide and acrolein
MELPHALAN HO2C
Melphalan - Alkeran®
dihyfrofolate reductase
Folic acid Tetrahydrofolate
(FH2) (FH4)
• 6-Mercaptopurine
• 6-Thioguanine
• Fludarabine Phosphate
• Cladribine
6-Mercaptopurine, 6-MP
Resistance
• Decrease drug activation by HGPRTase
• Increase inactivation by alkaline phosphatase
DRUG NOTES t1/2 Elimn
HPGRTase
6-Thioguanine 6- thioguaninosine-
(6-TG) 5-monophospahate
(6-TGMP)
• Fluorouracil (5-FU)
• Cytarabine
• Gemcitabine
• Capecitabine
Fluorouracil, 5-FU
80%
excreted
in urine
NATURAL PRODUCTS
ETOPOSIDE &
TENIPOSIDE Etoposide…can be oral or IV admin Biphasic: Mainly via
Teniposide … IV admin, more potent 11.5 hrs, kidneys
Toxicity: mild nausea, alopecia, allergic 72 hours
reaction, gastrointestinal irritants and bone
marrow suppression
Clinical use:
Etoposide- is used in testicular (in
combination with cisplatin) and ovarian germ
cell cancers, small lung cancers, acute
lymphoblastic leukemia
Teniposide-is used mainly in pediatric
cancers, particularly acute lymhoblastic
leukemia and are used in combination with
citarabine, vincristine and prednisone
CAMPTOTHECINS
First isolated from the bark and stem of Camptotheca acuminata
(Camptotheca, Happy tree), a tree native to China used as a cancer treatment
in Traditional Chinese Medicine
• Camptothecin(parent)
• Derivatives:
• Topotecan, Irinotecan
CAMPTOTHECINS-MOA
TOPOTECAN &
IRINOTECAN IV 2-3 hrs Topotecan is
35% PPB eliminated
renally
Toxicity: Irinotecan
and its
Topotecan- includes neutropenia, metabolite
thrombocytopenia, anemia are
Irinotecan- Severe diarrhea, eliminated
myelosuppression in bile and
faeces
Clinical use:
Topotecan- Second-line therapy for advanced
ovarian cancer (cisplatin-resistant), and small
cell lung cancer
Irinotecan- Colon and Rectal cancer
TAXANES
• Paclitaxel (Taxol)
• Docetaxel
Clinical use:
Paclitaxel- therapy against carcinomas of the
breast, ovary, lung, and head and neck (used
in combination with cisplatin)
Docetaxel- therapy against advanced breast
cancer
ANTITUMOR ANTIBIOTICS
• Substances of microbial origin that prevent
mammalian cell division
• Corticosteroids: Prednisone
• Gonadal Hormone Antagonists: Tamoxifen, Flutamide
• Gonadotropin-Releasing Hormone(GnRH) Analogs:
Leuprolide(Lupron, Eligard, Viadur), Goserelin(Zoladex)
and Nafarelin
Gonadal Hormone Antagonists-
MOA
Tamoxifen
• Selective estrogen receptor modulator(SERM)
• Blocks the binding of estrogen to receptors of estrogen
sensitive cancer cells in breast tissue
• Directly inhibits in vitro growth of human breast cancer
cells that contain estrogen receptors
DRUG NOTES t1/2 Elimn
TAMOXIFEN
(Nolvadex) Admin. O Biphasic: Hepatic
Reaches peak plasma levels after 4–7 7–14 hrs metaboli
hours and 4–11 sm by
Concentrated in estrogen target days CYP 450
tissues(ovaries, uterus, vaginal enzymes
epithelium and breast Excreted
in faeces