Pharmacology of Anticancer Drugs

Thera 9

Alkylating Agents
Name MOA Use PK ADR
-Leukemias (DOC CLL) -PO only -Least toxic of nitrogen
-Lymphomas -99% plasma protein mustards
Chlorambucil bound (only 1% active) -Weekly blood counts
(Leukeran) -Extensive hepatic
metabolism to active
metabolite
-MANY*** -PO or IV -Cardiotoxicity
-Malignant lymphomas -Take on empty stomach -Non-vesicant
Cyclophosphamide Nitrogen Mustards:
-Mycosis fungoides and leukemias -Hemorrhagic cystitis
(Cytoxan, Neosar) alkylate DNA
-Severe RA
-Systemic Lupus erythematosus
Classwide ADR: -Germ cell testicular cancer -Powder for IV -Hemorrhagic cystitis
-Myelosuppression
(need urinalysis before each
(bone marrow
dose)
suppression
-CNS problems like confusion
Ifosfamide neutropenia)
and coma
(Ifex) -Carcinogen, -Vesicant
Mutagenic
-Teratogenic (use
-Teratogenic (use
contraception)
contraception)
-Vesicant -Hodgkin’s disease -IV only -Extravasation
*Use gloves when -Lymphosarcoma -Most reactive of all -Monitor renal, hepatic, bone
dispensing, can be -lymphocytic leukemia mustards marrow
Mechlorethamine absorbed thru skin -Mycosis fungoides
(Mustargen)
-Metastatic dz via intrapleural,
intraperitoneal, or intrapericardial
administration
-Palliative treatment of multiple -PO or IV -Severe bone marrow
myeloma and non-resectable -Dose adjust for renal suppression infection and
Melphalan
ovarian carcinoma failure bleeding
(Alkeran)
-Solid rather than liquid tumors like -Cause chromosomal
the rest abnormalities
Estrogen + nitrogen -Metastatic or progressive -PO only -Administer with caution in
mustard: estradiol carcinoma of prostate -No dairy foods, antacids hepatic failure
Estermustine
targets estrogen -Thrombosis
(Emcyt) -Hypertension
receptor rich prostate
carcinoma cells
-Lymphoma (Hodgkin and non- -IV -Bone marrow depression,
Hodgkins) -Must be given slowly delayed 6 weeks
Carmustine -Palliative treatment for brain -Highly lipid soluble (can -CNS depression
(BiCNU, Gliadel) tumors cross BBB) -Renal toxicity
-Multiple myeloma -Do not give more often
-GI carcinoma than Q6 weeks
Nitrosureas: DNA -Lymphoma (Hodgkin and non- -PO -Bone marrow depression,
damage Hodgkins) -Highly lipid soluble (50% delayed 6 weeks
Lomustine
-Brain tumors higher CNS levels) -Nausea and vomiting
(CeeNu)
-Malignant melanoma -Take on empty stomach -Nephrotoxicity
-Epidermoid carcinoma of lung -Nerve dysfunction
-Pancreatic cancer -IV -Nausea and vomiting
Streptozotocin -Nephrotoxicity
-Liver toxicity
-DOC for palliative tx of chronic -Well tolerated
myelogenous leukemia (CML) -Severe myelosuppresion
-Bone marrow ablation before BMT (D/C at first sign), usually
Busulfan
rec. allopurinol bc you get
(Myleran, Busulfex)
tumor lysis syndrome (DNA
Alkyl sulfonates breaks down uric acid
renal failure)
-Palliative tx of recurrent or -PO -Neurotoxicity
Altretamine
persistent ovarian cancer following -Prodrug -Myelosuppresion (blood
(Hexalen) first line therapy counts Q month)
Thiotepa Aziridines: alkylates -Adenocarcinoma of breast or ovary -IV -Myelosuppresion (D/C if
(Thioplex) ethyleneimine radical -Control of intracavity effusions -Renally and hepatically drop in WBC or Plt, Monitor
disrupting DNA -Urinary bladder papillary dose adjusted CBC for 3 weeks following
carcinoma cessation of therapy)
Pharmacology of Anticancer Drugs
Thera 9
-Lymphomas
Methylhydrazines: -Metastatic malignant melanoma -IV only -Myelosuppression
Methylates purines -Hodgkin’s dz -Hepatic necrosis
Dacarbazine and inhibits DNA
(DTIC-Dome) synthesis, also reacts
with protein thiol
groups
Imidazotetrazines: -Refractory anaplastic astrocytoma -PO only -Myelosuppression
prodrug methylates not responding to nitrosurea and -Do not open capsules -N/V
Temozolomide
guanine-rich regions procarbazine -Take on empty stomach -Caution in renal and hepatic
(Temodar)
of DNA responsible impairment
for
initiating transcription
Cisplatin -Testicular, ovarian, bladder -Dose adjust based on -Bone marrow suppression
(Platinol-AQ) metastatic cancer renal, plt, neutrophils (dose related)
-Ovarian carcinoma -Faster conversion from -Hepatotoxicity
Carboplatin Platinums: prodrug prodrug active -Intractable nausea and
(Paraplatin)  DNA crosslinking -Dose adjust based on vomiting (carb has less)
renal, plt, neutrophils -Renal damage
Oxaliplatin -Ototoxicity
(Eloxatin) -Anaphylaxis
Antibiotics
Actinomycin D: -Wilm’s tumor -IV (peptide) -Extremly corrosive to
Intercalates DNA -Rhabdomyosarcoma -t1/2 = 36 hrs soft tissues
between adjacent -Choriocarcinoma -Min metabolism (extravasation): veno-
guanine-cytosine -Ewing’s sarcoma -Excreted in urine/feces occlusive disease
Dactinomycin
pairs, binds at -Peds sarcoma (Gestational -Myelosuppression
(Cosmegen)
transcription initiation trophoblastic neoplasia) (Anemia)
complex and prevents -Potentiates radiation
elongation by RNA toxicity, carcinogen
polymerase
-Malignant tumors in whom -IV only -Hypocalcemia
successful treatment by -Bleeding disorders
Unclear, but likely surgery and/or radiation is not -Liver and Kidney Toxicity
Plicamycin
through binding DNA possible
(Mithracin)
via Mg complex -Testicular CA
-Paget’s dz of bone
-Management of hypercalcemia
(rare)
Intercalates DNA and -Hodgkin’s lymphoma -IV, IM, SC, intrapleurally -Minimal
produces iron free -Squamous cell carcinomas -Not PO bc peptide myelosuppression
radicals , binds DNA -Testicular cell cancer (very good) -T ½ = 2h -Pulmonary fibrosis
single and double -Metabolized by (pneumonitis)
Bleomycin
strand breaks via aminopeptidase -Skin fibrosis
(Blenoxane)
oxidation of DNA- -Excreted by urine -Blistering
bleomycin-Fe complex, -Anaphylaxis
followed by radical
formation
-Crosslinking guanine -Disseminated carcinoma of -IV only -Bone marrow suppression
Mitomycin
and cytosine residues the stomach and pancreas -Hepatic metabolism (leucopenia,
(Mutamycin) -Does NOT intercalate thrombocytopenia)
-Acute non-lymphocytic leukemia -IV only -Severe Bone marrow
Anthracenedione: and other leukemias -renal and hepatobiliary suppression
Mitoxanrone
unclear but likely -Off label: Breast Ca, non- excretion -Cardiac toxicity with
(Novantrone)
through intercalation Hodgkin’s lymphoma CHF and dec LVEF
-Blue/green urine
Anthracyclines: see Topoisomerase Inhibitors
Antimetabolites
Folic Antagonist: binds -Acute lymphocytic leukemia -PO, IT, IM -Leucovorin =
dihydrofolate -Brest CA -Do not take with food tetrahydrofolic acid, can
reductase prevents -Head and Neck CA -Avoid alcohol, salicylates, help with MTX toxicity
tetrahydrofolic acid -Lung CA sun exposure -Bone marrow suppression
formation (active form) -Control of disabling psoriasis - MTX is metabolized to -Hepatotoxicity
Methotrexate
-RA MTX-polyglutamates -Diarrhea
-Off-label: non-metastatic (MTX-PG) by foly- -Irreversible Lung dz
osteocarcinoma polyglutamate synthetase
(FRGS), absence of MTX-
PG = resistance
Trimetrexate
Etotrexate
Pharmacology of Anticancer Drugs
Thera 9
Pemetrexed
Thioguanine -Acute nonlymphocytic leukemia -Thiopurine -Myelosuppression
-ALL methyltransferase (TPMT) -N/V/D
-AML inactivates thiopurines -Mucositis
Mercaptopurine
and polymorphism for
(Purinethol)
low TPMT increased
toxicity
Purine Nucleoside -Hairy cell leukemia (DOC) -Myelosuppression
Cladribine Analogs: -Fever
(Leustatin) -Nephrotoxicity
-Neurotoxicity
-CLL -Myelosuppression
Fludribine -Blindness
(Fludara) -Coma
-Death
-Synergistic activity with MTX -DPD deficiency  dec 5- -Myelosuppression only at
-Colorectal carcinoma (single agent) FU breakdownmore high doses (5 g/day)
5-Fluorouracil
-Breast, head/neck (combo) toxic metabolites, likely -N/V/D
to have toxicities -Mucositis
(N/V/D) -Hand and foot syndrome
-Metastatic breast cancer -PO prodrug 5-FU -Elderly are more
Pyrimidine Nucleoside
sensitive to 5-FU due to
Capecitabine Analogs
hepatic and renal
(Xelado)
impairment
-DDI with warfarin
-Leukemia -IV only -Myelosuppression
Gemcitabin -Pancreatic -Caution in hepatic/renal -Paresthesias
(Gemzar)- dFdC -non-small lung cancer failure -Severe rash
-solid tumor activity
Topoisomerase Inhibitors
-Solid tumors -Renally and heapatically -Very cardiotoxic can
Doxorubicin
-Disseminated neoplastic dz adjusted lead to CHF (dose
(Adriamycin, Rubex;
-Karposi’s sarcoma depndent, Free radicals
Liposome = Doxil)
form with iron, liposomal
Anthracyclines: 1.
Daunorubicin -HCl: Leukemia -IV only, NEVER IT less, Dexrazoxane rescue)
Intercalation of DNA
(Generic = -Liposomal: Advanced HIV- -Liposomal preparations -Myelosuppression
2. Inhibition of
HCl; Liposome associated Karposi’s sarcoma cannot be substituted -Mucositis
topoisomerase II, 3.
= -Hair loss
DaunoXome ) generates free radicals
-Nausea/Vomiting
Idarubicin 4. Alkylation of -Intravesical bladder instillation -Extravaation
(Idamycin) DNA/RNA -Acute myeloid leukemia -red urine and sweat
-Breast Cancer -Liposomal: lipids
Epirubicin prostaglandins and cause
(Ellence) excruciating back pain
-Ewing’s sarcoma -PO or IV -Myelosuppression
-Lung CA -95% bound to albumin- -N/V
-Testicular CA albumin acts as a depot -Alopecia
Etopside -Lymphoma -Cross BBB
Epipodophyllotoxins: -Non-lymphocytic leukemia -Metabolized in liver to
Pure toposiomerase II -Glioblastoma less active
inhibitor, stabilizes -Renal/fecal excretion
topo II-DNA adducts -IV only
resulting in DNA breaks -99% bound to albumin
-Cross BBB
Tenopside
-Metabolized in liver to
less active
-Renal/fecal excretion
-Metastatic colon, rectal CA -prodrug SN-38 -Myelosuppression
(active) SN-38G -Severe diarrhea (I ran
Irinotecan Topoisomerase I
(metabolite), dec SN-38G to the can)
inhibitor associated with GI toxicity
Topotecan -Metastatic ovarian CA -Myelosuppression
Microtubule Inhibitors
Vinca Alkaloids: binds -Lymphomas -IV only -Irreversible
Vinblastine to tubulin dimmer and -Hodgkin’s dz -Metabolized by liver neurological damage
disrupts microtubule -Non-Hodgkin’s lymphoma -Biliary/fecal excretion (never administer to
Vincristine polymerization during -Multiple myeloma -IV only spinal canal, relb < crist)
mitosis -Soft tissue sarcomas -Metabolized by liver -N/V
-Osteogenic sarcoma -Biliary/fecal excretion -Alopecia
Pharmacology of Anticancer Drugs
Thera 9
-Brain tumor -PO and IV -Myelosuppression (blast)
Vinorelbine -Acute leukemia -Metabolized by liver -Peripheral neuritis (cris)
-Non-small lung cancer -Biliary/fecal excretion -Granulocytopenia (relb)
Taxanes: stabilize -Lung, ovarian, breast, head -IV -Dose related
Paclitaxel microtubules and and neck CA -3 weeks or weekly -Docexatel > Paclitaxel
prevent -Advanced Kaposi’s -t ½ = 6, but can -Myelosuppression
depolymerization after accumulate in tissues for -Neurotoxicity (peripheral
mitosis, induces -Docetaxel approved for locally long time neuropathy)
apoptosis by binding advanced or metastatic breast -Metabolized by liver -Fluid retention
to Bcl-2 and arresting or non small-cell lung cancer -Fecal/renal excretion
function (after failing anthracyclic)
Docetaxel
Paclitael also induces
expression of TNF-
alpha and inhibits
angiogenesis
Hormonal Agents
Selective Estrogen -Metastatic breast CA Tx -PO -Hot flashes
Receptor Modulator -PPX Breast cancer -Rapid absorption in GI -Fluid retention
(SERM) will bind to -Metabolized in liver -Nausea
estrogen R and  -Main metabolite in
Tamoxifen
conformational plasma
change cannot
transcribe cancer
producing proteins
-Breast, renal cell, -F = 90% -Adrenal insufficiency
endometrial carcinoma -Strongly bound to
Synthetic progestin, -Stimulate appetite in AIDSs pt plasma proteins
Megestrol
MOA unknown -Concentrates in adipose
-Metabolized in liver
-Renal elimination
Nonsteroidal -Metastatic prostatic carcinoma -PO -Gynecomastia
antiandrogen: -NOT effective for -F = 90% -Mild liver injury
Inhibition of uptake hormonally dependent dz -95% bound to plasma -GI problems
and/or nuclear binding (not a steroid) proteins
Flutamide
of testosterone and -Prodrug, metabolized
dihydrotestosterone in quickly by liver to
prostatic tissue to active form
androgen R -Excreted by kidneys

Bicalutamide Used in combo with

LHRH antagonists
Non-steroid -Metastatic breast cancer -PO -Dizziness
Aromatase inhibitor: (Estrogen R and progesterone R -Lethargy
inhibits conversion of positive) -Visual blurring
cholesterol to -Rash
pregnolone and -Hepatotoxicity
Aminoglutethimide androstenedione to -Hypothyroidism
estrone/estradiol, -Requires gluc- and
reduces biosynthesis of mineralcorticoid
glucocorticoids, replacement therapy
mineralocorticoids,
estrogens, androgens
Like aminoglutethimide -Advanced ER and PR positive -F = 85% -Does not require gluc
but does not inhibit breast cancer no longer -Metabolized by liver and mineralocorticoid
Anastraole
adrenal steroid responsive to tamoxifen replacement therapy
synthesis
Steroid Aromatiase -PO
inhibitor: inhibits -No cross-resistance with
Exemestane
irreversibly acting as other non-steroidal
a suicide substrate aromatase inhibitors
Leuprolide -Metastatic carcinoma of the -IM or patch -Gynecomastia
Gonadotropin-
(Lupron) prostate -Good F -Loss of libido, impotence
Releasing Hormone
-Hormone receptor-positive breast -T ½ = 2-4 hr -Edema
Goserelin (GnRH) Antagonists:
cancer -Renally excreted -Thromboembolism
(Zoladex) super agonists of GnRH -Metabolized by peptides
Tyrosine Kinase Inhibitors
Imatinib Inhibits c-Abl, C-kit, and -Leukemia -PO -Low toxicity
Pharmacology of Anticancer Drugs
Thera 9
-Other cancers -F = 98% -Many CML patients
-Metabolized by liver relapse due to secondary
(Gleevec) PDGF-R
CYPs mutations in ATP
N-demethylated binding
piperazine region of kinase
CML resistant to -T1/2 = 18h, metabolite -Favorable safety profile
Nilotinib Imatinib 40h -Potential heart
-Secreted in bile/feces complications
Inhibits all BCR-Abl
Dsatinib
mutants except T315I
-VEGFR Inhibitors: -Renal cell carcionoma (RCC) -F 38-49%, unaffected -Very mild
Inhibits VEGFR  -Imatinib-resistant GI stromal by food -Fatigue
reduced tumor tumor (GIST) -Metabolized by CYPs in -Nausea, diarrhea, anorexia
vascularization and liver to N-desetylated -HTN
Sunitinib
cancer cell death metabolite (active) -Stomatitis (inflammation
(Sutent)
-Inhibits C-kit RTK (C- -T ½ = 40-50 hr, 80-110 of mucus lining of any of
kit involved in driving for metabolite the structures in the mouth
GI stromal cell tumors), -Fecal/renal excretion
RET, CSF-1R, flt3
-Bind to active site and -Renal cell carcinoma
Sorafenib
has little structural -Advanced primary liver
(Nexavar)
homology to sunitinib cancer (HCC)
-Binds VEGFR 1-3,
PDGFR- alpha/beta, C-
Pazopanib
kit
(Votrient)
-Little structural
homology to sunitinib
-Locally or advanced metastatic -250 mg PO -Because it is selective,
EGFR Inhibitors: non-small cell lung cancer -F = 59% the tolerability profile is
Gefitinib
Selective inhibitor of (NSCLC) in patients who -Metabolized by CYPs in favorable
(Iressa)
EGFR tyrosine kinase previously had chemo liver -Acne, Dry skin
domain Inhibits Akt -NSCLC EGFR sensitizing -Excreted thru feces -N/V/D
Erlotinib mediated anti-apoptotic mutations (1st line) -150 mg PO -Anorexia
(Tarceva) pathway preventing -Empty stomach -Ocular toicity
Afatinib malignant cells to grow -40 mg PO -Stomatitis
(Gilotrif)
Osimertinib
-Locally or advanced -250 mg PO BID in 28 day -Vision disorder
metastatic NSCL with ALK cycle -N/V/D, constipation
positive -Edema
Crizotinib ALK inhibitor -LFT elevation
(Xalkori) (anaplastic lymphom a -Transiet changes in
kinase): inhibits ROS1 renal function
rearrangement and -NEutreopnia
MET amplification -Pneumonitis
-ALK positive: ALK-inhibitor naïve -750 mg PO daily -N/V/D
Ceritinib
or those that progressed -LFT inc
(Zykadia) -Interstitial lung disease
on crizotinib
Monoclonal Antibodies
Anti-HER2: Binds to -Metastatic breast cancer -IV -EXPENSVIE
cells over-expressing -T ½ = 2-12 days -Cardiac dysfunction
HER2 and prevents -Metabolism unknown -Risk of cardiomyopathy
dimerization and (esp when combined with
activation, can cause anthracyclines)
Trastuzumab
some R to be
(Herceptin)
endocytosed, drawn
into cell, away from cell
surface, mediates ADCC
via NK cells and
monocytes
Bevacizumab Anti- VEGF-A: Blocks -Metastatic cancers -IV -EXPENSIVE
(Avastin) several VEGF receptors -Glioblastoma multiforme -T ½ = 20 days (typical of -Impairs wound healing
leading to reduced -Can also be used for vascular- antibodies) (not allowed until 28 days
tumor vascularization related dz like age-related -Metabolized through RES after surgery
and cancer cell death macular degeneration (AMD) and -Bleeding
diabetic retinopathy -Neutropenia
-Hypertension
-Proteinuria
-Impair Fertility
Pharmacology of Anticancer Drugs
Thera 9
-GI perforations
-Arterial Thromboembolic
Events

Anti-CD20: Blocks B- -Leukemia -IV -Infusion reactions (may be

cell activation and -Lymphomas -T ½ = 30-400 hrs severe)
proliferation -Autimmune disorders -Excretion and -Cardiac arrest
metabolism through -Tumor lysis
Rituximab
phagocytosis and RES syndrome acute renal
(Rituxan)
failure requiring dialysis
-Viral infections
(progressive multifocal
leukoenceophalopathy)
-Chronic lymphocytic leukemia
Alemtuzumab Anti-CD52: kills mature (CLL)
(Campath) lynphocytes -Cutaneous T-cell lymphoma (CTCL)
-T- cell lymphoma
-Metastatic NSCLC for PD- -2 mg/kig IV infusion -immune related
L1 positive after failure of over 30 minu Q3weeks -Colitis
prior platinum-based -Pneumonitis
Pembrolizumab treatment -Hyper/hypothyroid
Anti PD-L1
(Keytruda) -Nephritis
-Vasculitis
-Pancreatitis
-Sepsis
-Follicular lymphoma, specifically -Give naked antibody -Severe thrombocytopenia
Radio
Tositumomab indicated in patients with relapsed first then conjugated to and neutropenia
immunotherapy: Anti-
(Bexxar) or chemotherapy/rituxan refractory 131-
I
CD20 + 131-iodine follicular lymphoma
Radio Immunotherapy: -B cell non-Hodgkin’s luymphoma -Severe and prolonged
Ibritumomab
Anti-CD20 + tiuxetan cyotpenias
tiuxetan
(chelator)+ 90Y, cell death
(Zevalin)
via ADCC, CDC, Apoptosis
Other Targeted Therapies
Ubiquitin Proteasome -Multiple myeloma -IV (tripeptide) -Fatigue, generalized
Inhibitor: Highly -Mantle cell myeloma -Peak after 30 min, weakness
selective reversible Rapidly cleared after -Peripheral neuropathy
inhibitor of 26S IV -N/V/D
Bortezomib
proteasome, boron -Low platelet count
(Velcade)
atom binds to catalytic
site  prevent
degradation of
apoptosis proteins
HDAC Inhibitor: -Cutaneous T cell lymphoma -PO -Pulmonary embolism
mimics lysine side (CTCL) when dz persists, gets -Metabolized by liver -GI symptoms
Vorinostat chain, hydroxamic acid worse, or comes back after via glucuronidation and -Fatigue, chills
(Zolinza) binds to zinc of catalytic treatment with other medicines oxidation (NO CYPS) to -Myelosuppression
site of deacetylase inactive metabolites -Taste disorders
enzyme
-Cutaneous T cell lymphoma -IV only (depsi peptide) -N/V, loss of appetite
HDAC Inhibitor:
(CTCL) in patients who have -T ½ = 3 hrs -Fatigue
Romidepsin prodrug thiol binds
received at least 1 prior systemic -92-94% protein bound -Myelosuppression
(Istodax) zinc reversibly in
therapy mostly to AAG -Metabolic disturbances
catalytic site of HDAC -Metabolized by CYPs -Taste disorders