Alkylating Agents

Type of Agents Non-proprietary name Disease Mode of action Toxicity Method of Resistance
Nitrogen Mustard Meclorethamine via IV Hodgkins disease Non phase specific-forms adducts (corss links)
with DNA via covalent bonds (esp. N-7 guanine)
Bifunctional alkylation
Affects dividing cells
GIT, Gonadal, and pulmonary toxicity
Immunosuppression
Inactivation by electron rich
molecules: Glutathione
Repair of DNA damage produced
by agent
Increased aldehyde
dehydrogenase
Cyclophosphamide via IV or
orally
Hodgkins disease, non-hodgkins, ALL, CLL, Same+ activated by cyt p450 phosphoramide
mustard + acrolein
Phosphoramidehas anti-tumor effect
Acrolein causes hemorrhagic cystitis
Fulminant cardiac toxicity at high
doses

Ifosfamide Non Hidgkins, meyloma, neuroblastoma, breast, ovary,
lung, cervix, testis cancer, wilms tumor, soft tissue
sarcoma
Monofunctional alkylation.:. needs higher doses Greater extent of hemorrhagic
cystitis
Mesna used to prevent this

Melphalan Multiple myeloma and bone transplantation Transported via amino acid transport system
Chlorambucil via oral CLL, macrogloulinemia (chronic B-cell lymphocytic
leukemia)

Alkyl Sulfonate Busulfan via oral and iv Chronic myelogenous leukemia, bone marrow
transplantation
Bifunctionally alkylates Venocclusive disease of the liver
Nitrosoureas Carmustine (BCNU) via wafers Hodgkins disease, non-hodgkins, glioblastoma Alkylation as 06 guanine
Crosses BBB
Phenobarbital increases clearance
Delayed myelosuppresion
Decrbazine (DTIC) Malginant melanoma, Hodgkins disease, soft tissue
sarcomas, melanomas
Alkylation at 06 guanine
ABVD regimen for Hodgkins
Generates active metabolite MITC
Fever and Malaise cured by taking
acetominophin
Photosensitive

Triazenes Temozolomide Malignant gliomas Generates MITC, cross BBB
Either as single agent or in combo with radiation
therapy


Subject: Pharmacology
Topic: Cancer Chemotherapy
Lecturer: Dr. Dexter Santos
Date of Lecture: July 18, 2012
Transcriptionist: GemmaRegina
Pages: 6

Antimetabolites
Type of agent Nonproprietary names Disease Mode of action Toxicity Method of resistance
Folic acid analogs Methotrexate via intrathecal,
IV, oral
ALL, choriocarcinoma, breast,
lung, head and neck, lung
cancer, osteogenic sacroma
Specific for S phase
Inhibits DHR, blocks
thymidylate and purine
synthesis
Bone marrow suppression DHFR mutation
Unable to polyglutamate
methotrexate
Increased DHFR conc
Premetrexed Mesothelioma, lung cancer Inhibits tumor enzymes and
GFRT
Mutlifolate antiagonist
Needs B vitamins esp. folic
acid to limit toxicity

Pyrimidine analogs Fluorouracil (5-FU) Breast, colon, esophageal,
stomach, pancreas, head and
neck, premalignant skin lesion
Inhibits thymidylate synthesis
by inhibiting thymidylate
synthase (inc with leucorvin)
Inactivated by DPD in liver
Myelosuppresion
Mucositis and GI SE
photosensitive

Capecitabine via oral Breast, colon, esophageal,
stomach, pancreas, head and
neck, premalignant skin lesion
Pro drug of 5-FU activated by
thymidine phosphorylase

Cytarabine via IV, intrathecal Acute myelogenous
lymphoma and ALL, non-
hodgkins
Inhibits DNA synthesis
Converted to 5
monophosphate mucleotide
by deoxycytidine kinase
Inactivated by ycytidine
deaminase
Myelosuppression:
Anemia, thrombocytopenia,
leukopenia
Neurotoxicity
Conjunctivitis
GIT disturbances
Deficiency in deixycytidine
kinase
Increased cytidine deaminase
Reduced affinity for DNA
polymerase
Gemcitabine Pancreatic, ovarian, lung
cancer
Inhibits DNA synthesis via
inhibition of DNA pol, and
ribonucleotide reductase
Causes strand termination
Myelosupression
No vomiting or hair loss

Purine analogs and related
inhibitors
Mercaptopurine (6-MP) ALL, Acute myelogenous
leukemia, small cell non-
hodgkins
Inhibits purine ring
biosynthesis (HGPRT
converted into
ribonucleotides)
inhibits DNA synthesis


Deficiency in HGPRT
Thioguanine ALL
Fludarabine CLL Depletes CD-4 helper Tcells
Cladribine Hairy cell leukemia Depletes CD-4 helper Tcells

Natural Products
Type of agent Nonproprietary names Disease Mode of Action Toxicity Resistance Mechanisms
Vinca Alkaloids Vincristine ALL, neuroblastoma, Wilms tumor,
rhabdomyosarcoma, Hodgkins and
non-hodgkins
M-phase specific inhibits function
of tubules arrest at M-phase
Vesicant-burns entire hand
Neurotoxic-affects nerve supply of
GIT causing constipation
Increased P-glycoprotein
expression
Vinblastine Hodgkins, non-hodgkins, testicular
cancer
M-phase specific inhibits function
of tubules arrest at M-phase
Vesicant-burns entire hand
myelosuppression
Increased P-glycoprotein
expression
Vinorelbine Breast and lung cancer M-phase specific inhibits function
of tubules arrest at M-phase
Vesicant-burns entire hand

Increased P-glycoprotein
expression
Taxanes Paclitaxel Breast, lung , prostate, head and
neck, ovarian, bladder cancers
M-phase specific
Acts in beta-tubulin to prevent
separation of chromatids
Promotes microtubule formation
High incidence of allergic reactions
(due to vehicle formulation)
Pre-meds: steroids and anti-
histamines
Glove-stocking neuropathy

Docetaxel More pronounced neutropenia
Campothecins Irinotecan Colon Cancer S-phase specific
Block topoisomerase function
stabilized topoisomerase I
accumulation of ssDNA
irrepairable dsDNA
Excreted via Glucorination UGT1A1
Active metabolite: SN38
Neutropenia
Diarrhea
Myelosupression
Acute phase cholinergic syndrome:
prophylactic using atropine
Delayed phase diarrhea: using
loperamide

Topotecan Ovarian and small cell lung cancers
Epiphodophyllotoxins Etoposide Testis, small cell lung and other
lung ca, breast cancer, hodgkins,
non-hodgkins, lymphomas, acute
myelogenous leukemia, kaposis
sarcoma
Block topoisomerase II
similar MOA as that of
camptothecins
Those with low albumin risk
increased toxicity due to inc free
fraction
Secondary malignancy


Anthracyclines Doxorubicin Lymphomas, leukemias, breast ca,
sarcomas, SCLCA
Binds with topoisomerase II

Generates free radicals
cardiotoxicity

Liposomal Doxorubicin Ovarian ca and lymphomas Less cardiotoxic, less neutropenia
Anthracenedione Bleomycin via IV, IM, intravesicular Testis, and cervical ca, Hodgkins,
and non-hodgkins
Oxidative damage to deoxyribose
of thymidylate leading to ss and ds
breaks in DNA
Pulmonary fibrosis: decline in CO2
Cutaneous toxcitiy:
hyperpigmentation and keratosis

Mitomycin via IV Anal cancer Bifunctional alkylating agent after
enzymatic alterations
Cross links with N6 of adenine and
O6 & N7 guanine
Myelosuppression
Hemolytic uremic syndrome




Platinum compounds and others
Type of Agent Nonproprietary names Disease Mechanism of Action Toxicity Methods of Resistance
Platinum compounds Cisplatin via IV Testicular, ovarian, bladder,
esophageal, lung, head and
neck, colon and breast ca
Forms adducts with DNA
Enters cells via active
transporter
Needs to be aquated
Renal toxicity: prevented by
hydration and diuresis
Myelosuppression
Ototoxicity-high frequency of
hearing loss
Electrolyte abnormality
Most emetogenic
chemotherapeutic drug
Defects or deficiencies in
mismatch repair enzymes
(MMR)
Increased activity of
nucleotide excision repair
Not affected by P-
glycoprotein
Carboplatin Better tolerated, less
emetogenic, less toxic
More pronounced
neutropenia

Oxaliplatin Less neutropenia, nephron
and neurotoxic but more
neurpathic
Least effected by MMR
mutations

Enzymes L-asparaginase ALL Hydrolysis of circulating
asparagine to aspartic acid
and ammonia no
asparagine synthase for
malignant cell
Hypersensitivity reactions
(foreign protein)
Inhibition of protein synthesis
causes hyperglycemia,
clotting abnormalities,
hypoalbuminemia

Substituted Urea Hydroxyurea Chronic myelogenous
leukemia, polycythemia vera,
essential thrombocytosis
Inhibits ribonucleoside
diphosphate reductase w/c
catalyzes RL step of
conversion of ribonucleotides
into deoxy form
Myelosuppression
Leukopenia
thrombocyotpenia

Mitotane Adrenocortical carcinoma Chemically similar to DDT
Destroys adrenalcortical cells
Anorexia, nausea, depletion
of endogenous
corticosteroids




Hormonal Agents and Biologic Response Modifiers
Type of Agent Nonproprietary name Disease Mechanism of Action Toxicity Method of Resistance
Hormonal Adrenocorticosteroids
(prednisone, dexamethasone)
ALL, CLL, Hodgkins and non-
hodgkins, breast ca, multiple
myeloma
Promote apoptosis Immunosuppression, glucose
intolerance, osteoporosis,
water retention, GI ulcers

Aromatase inhibitors
(letrozole, anastrozole)
Breast ca Inhibits aromatase enzyme
which converts androgens
into estrogen
For post-menopausal
Bone mineral density
Bone pains, increased
fracture rates

Anti-estrogens (Tamoxifen,
toremiene)
Breast ca Binds to estrogen receptor
w/c eventually decreases
autocrine stimulation of
breast ca cells
For pre and post menopausal
Thromobosis
Endometrial ca
Hot flashes,
Nausea and vomiting
Menstrual irregularities

GnRH analogs (leuprolide,
gosserelin)
Breast and prostate ca Stimulates FSH and LH flare
negative feed back
inhibition
Flare reaction
Anti-androgens (flutamide,
casodex)
Prostate ca Binds to androgen receptors
causing complete blockade of
androgen
Decreased libido
Hot flashes
Gynecomastia & mastodynia

Biologic Response modifiers Interleukin-2 Melanoma, renal cell
carcinoma, AML
Indirectly cytotoxic
Expands cytotoxic T-cell
response
Hypotension, peripheral
edema, azotemia

G-CSF (fligrastim/lenograstim) Prophylaxis for chemotherapy
induce neutropenia
Expands neutrophil precursor
population
Fever, chills







Targetted Therapies
Type of Agent Nonproprietary names Disease Mechanism of Action Side Effects
Monoclonal antibodies Trastuzumab Breast cancer Her2 CHF+ hypersensitivity
reaction

Bevacizumab Inhibit angiogenesis Vegf ligand Hypertension, bleeding,
proteinuria + hypersensitivity
reaction

Cetuximab Colorectal, heand and neck ca EGFR Skin rashes + hypersensitivity
reaction

Panitumomab Colorectal ca EGFR + hypersensitivity reaction
Rituximab B-cell lymphomas CD20 + hypersensitivity reaction
Tyrosine Kinase inhibitors Imatinib Chronic myelogenous
leukemia, GIST
Bcr-abl TKI & CD117 Rashes, asthenia, weakness
Gefitinib NSCLca EGFR Rashes, asthenia, weakness
Erllotinib NSCLca EGR Rashes, asthenia, weakness
Sunitinib Renal cell carcinoma Multikinase Rashes, asthenia, weakness
Sorafenib Renal and liver cancer Multikinase Rashes, asthenia, weakness
Lapatinib Breast, head and neck ca EGFR Rashes, asthenia, weakness
Proteasome Inhibitors Bortezomib Multiply myelomas NF kappa-B attached to IK-B
to prevent self proliferation,
angiogenesis and cell survival

mTOR inhibitors Temsirolimus, everolimus Renal cancer Se/thre protein kinase
involving signal transduction



GR: Good luck fliggies sa pharma review!
This tranx was a mix of past ppts from doc dex+past tranx+ smattering of Goodman and Gilmans.
for a complete review please read your very expensive books.
Well behaved women seldom make history Laurel Thatcher Ulrich
Drugs w/c can cross BB:
High doses of methotrexate
Carmustine
Temozolomide
Treniposide
hydroxyurea