a

Y
y
pa
Je
s
vi
Lec 3: Chemotherapeutic Drugs by Dr. Alabastro June 29, 2010
a
M *A crucial component of the cell’s machinery for organizing
vs and dividing the chromosomes are the microtubules.
Re
I. Cancer
ai
A. Etiology
M
B. Review of Mitosis
n
C. Factors affecting tumor growth
II. Chemotherapy
Re
A. Indications
y
B. Cintraindications
o
III. Chemotherapeutic Drugs
Ic
A. Cell-cycle Specific
F.
B. Cell-cycle Nonspecific
ul
IV. Alkylating Agents
Pa
V. Antimetabolites
vs
VI. Antibiotics Anticancer Agents
Vi
VII. Natural products (mitotic disrupters)
ne
le VIII. Natural products (microtubule polymer stabilizer)
IX. Natural products (epipodophyllotoxins) • If a cell expresses normal p53 protein, DNA damage
Ar
a X. Natural Products (Camptothecins)
activates a normal checkpoint function and damaged
ň XI. Hormone/ Hormones antagonists
cells undergo apoptosis, or programmed cell death, when
Ni XII. Drug Combinations
g they reach the G1/S boundary.
an • If the p53 gene product is mutated or absent and the
ad checkpoint function fails, damaged cells will not be
diverted to the apoptotic pathway but will proceed through
D Cancer
S phase.
er ETIOLOGY:
h • Checkpoints are between G1 to S and G2 to M.
ac • Disease of cells characterized by a shift in the control • DNA maintenance checkpoint includes (a) the DNA
e mechanisms that govern cell proliferation and damage checkpoints that recognize and respond to
T differentiation DNA damage, and (b) the DNA replication checkpoint
co • Smoke that monitors the fidelity of copying DNA.
Ri • Alcohol
ie • Ionizing radiation FACTORS AFFECTING TUMOR GROWTH
ck • Environmental exposure: asbestos, UV-B, electromagnetic • Cell cycle time – average time for a cell that has just
field
completed mitosis to grow, re-divide and again pass
•
Ni
Diet, habitus
through mitosis
• Oncogenic RNA viruses: human T-cell leukemia virus
ad
Gl (HTLV-1); AIDS (HIV1); retrovirus • Growth fraction – fraction of cells undergoing cell
Je
• Genetic: bcl-2 oncogenic amplification; tumor-suppressor division
nz gene damage (p53 gene) • Total number of cells in the population
Ay • Increase cell death rate
h THE CELL CYCLE
at An understanding of cell-cycle kinetics is essential for the SIGNIFICANCE
K proper use of antineoplastic agents. Many of the most • Cell cycle time
o effective cytotoxic agents act by damaging DNA. o determines the maximum growth rate of a
Jh tumor
h Prophase – nuclear membrane breaks down, mitotic spindle o does no determine drug sensitivity
forms, chromosomes condense
• Growth fraction
a
o contains portion of cells that are sensitive to
n
Metaphase – chromosomes condense at equator
drugs
e
Gi Anaphase – chromosomes segment in chromatids and • Total number of cells
o separate o index of how advanced the cancer is
Ed
Telophase – cell divides into parent and daughter cell • Increase cell death rate
e
difficult to measure; slows growth rate of many solid tumors
ll
ce
Jo
be Page 1 of 12
Jo
Iv
k
ar
STAGES OF TUMOR GROWTH • Prevention of resistant clones
M
• Lag phase – little tumor growth; cells are becoming multiple drugs with independent MOAs or alternating non-cross
el
h accustomed to new environment resistant combination
• Log phase – repeated doubling of cell number • Cytotoxicity to resting and dividing cells
ac
• Plateau phase – levelling off of cell doubling; most kill cells dividing slowly and those dividing actively
R
measurable cancers are in this phase • Biochemical enhancement of effect
”
equally effective drugs
“G
active agent w/ inactive agent (levamisole)
n
CAUSES OF OVERPRODUCTION OF CANCER CELLS •
h
Sanctuary access
•
Jo
Failure of abnormal cells to undergo apoptosis drug solubility or affinity of specific tissues for a particular drug
type
n
(programmed cell death)
•
Ia
• Inappropriate stimulation of cell proliferation of genetic Rescue
a
abnormalities one agent rescues the host from toxic effects of another drug
n
Ni • Abnormalities in tumor-suppressor genes (p53)
MODIFYING DRUG DOSAGE
• Tumor angiogenesis
• Therapy postponed in infection, persistent toxicity,
significant debility
INDICATIONS OF CHEMOTHERAPY
• Neutrophil count <2,000 or platelet count <120,000
• Cure certain malignancies
(increase interval)
• Palliate symptoms – benefits of treatment exceed side • Drugs which cause mucositis or diarrhea not given
effects until fully recovered
• Treat asymptomatic patients (treatable, rate of • Drugs that cause renal toxicity not administered
relapse decreased) unless creatinine clearance >55 ml/min (Mtx,
• Allow less mutilating surgery Cisplatin, Streptozocin)
• Doses of vinca alkaloids and anthracyclins reduced in
CONTRAINDICATIONS OF CHEMOTHERAPY hepatic impairment
• Inadequate facilities
• Survival unlikely even if tumor shrinkage is CHEMOTHERAPEUTIC DRUGS
accomplished I. ALKYLATING AGENTS
• Unlike to obtain benefits from drug because of severe • have a structure containing a bis(chloroethyl)amine,
debilitation ethyleneimine, or nitrosourea moiety
• Asymptomatic patients with slow-growing incurable
tumors FIVE MAJOR TYPES OF ALKYLATING AGENTS
(1) the nitrogen mustards;
Cell Cycle-Specific (CCS) Cell Cycle-Nonspecific (2) the ethyleneimines
Agents (CCNS) Agents (3) the alkyl sulfonates
Antimetabolites Alkylating agents (4) the nitrosoureas
Capecitabine Busulfan (5) the triazenes
Cladribine Carmustine
Cytarabine Cyclophosphamide A. Mechanism of Action
Fludarabine Lomustine
5-Fluorouracil (5-FU) Mechlorethamine • Alkylations of DNA within the nucleus
Gemcitabine Melphalan • Intramolecular cyclization that transfers an alkyl group
6-Mercaptopurine (6-MP) Thiotepa to a cellular constituent (target: guanine in DNA & RNA)
Methotrexate (MTX) Anthracyclines • Interactions can occur on a single strand or on both
6-Thioguanine (6-TG) Daunorubicin strands of DNA through cross-linking
Antitumor antibiotic Doxorubicin • Acquired resistance to one alkylating agent often but not
Bleomycin Epirubicin always impart cross-resistance to other alkylating agents
Epipodophyllotoxins Idarubicin • Resistance: increased capability to repair DNA lesions;
Etoposide Mitoxantrone decreased permeability of cell to the drug; increased
Teniposide Antitumor antibiotics production of glutathione which inactivates alkylating agents
Taxanes Dactinomycin
Albumin-bound paclitaxel Mitomycin
B. Pharmacologic Effects
Docetaxel Camptothecins
Paclitaxel Irinotecan • Direct vesicant effects (nitrogen mustards): can damage
Vinca alkaloids Topotecan tissues at the site of injection; irritants (cisplatin,
Vinblastine Platinum analogs dacarbazine)
Vincristine Carboplatin
Vinorelbine Cisplatin C. Toxicities
Oxaliplatin • Acute myelosuppression
• Cyclophosphamide has lesser effects on
EFFECTIVENESS OF COMBINATIONS platelet counts

Page 2 of 12
 • Busulfan suppresses all blood elements •Fludarabine- bone pains; muculoskeletal (cramps), no
• Highly toxic to dividing mucosal cells, leading alopecia; immunosuppression
to oral mucosal ulceration and intestinal
denudation • Exerted against rapidly dividing cells of the bone
• Nausea and vomiting marrow and GI epithelium ( Mucositis,
myelosuppression, and thrombocytopenia)
• Ifosfamide is the most neurotoxic of this class
• Toxic effects on the male and female • Pneumonitis
reproductive systems, causing an often • Hepatic fibrosis and cirrhosis
permanent amenorrhea
• Abortion and teratogenesis

Nitrosoureas III. ANTIBIOTICS ANTI-CANCER

A. Mechanism of Action
• MOA: bifunctional alkylating agent capable of • Bind with double-helical DNA with the transcription of
alkylation and carbamoylation DNA by RNA polymerase is blocked
• Cell cycle non-specific • Plicamycin complexes with Mg to DNA and blocks RNA
synthesis
• Non-cross resistant with other alkylating agents
• Mitomycin: cause cross links between complementary
• Highly lipid soluble strands of DNA that impair replication

• Capacity to cross blood-brain barrier

B. Pharmacologic Effects
• Delayed meylosuppressive effects (6-8 weeks);
streptozocin with minimal bone marrow toxicity • Used primarily in the acute leukemias
against human solid tumors
• Highly carcinogenic & mutagenic • Do not cross blood brain barrier exc. For
bleomycin which crosses poorly
• Carmustine (BCNJ) an irritant; pulmonary

• Streptozocin C. Toxicities
anorexia, blistering, hyperkeratosis of palms; no significant
o Sugar-containing nitrosourea myelosuppression; irritant (plicamycin); hepatotoxicity
(plicamycin)
o Effective in insulin-secreting islet cell
pancreatic carcinoma; non-hodgkin’s lymphoma;
carcinoid IV. NATURAL PRODUCTS
A. Mechanism of Action
o Nephrotoxicity
Vinca Alkaloids
II. ANTIMETABOLITES • Bind specifically to b-tubulin and to block its ability to
A. Mechanism of Action polymerize with a-tubulin into microtubules
Either inhibit critical enzymes involved in nucleic acid synthesis • Cell division is arrested in metaphase
or become incorporated into the nuclei acid and produce • Extensively metabolized by liver
incorrect codes
• Non-linear dose response curve (function of time & • Excreted mainly in bile; 15% in urine
concentration) e.g., 5 FU
• Myelosuppression is more of leucopenia
• Methotrexate & mercaptopurine have both oral and IV
preparation • All cause hair loss; areflexia
• Anti-folates & pyrimidine analogs act both on RNA &
DNA synthesis • *During metaphase, the cell pulls duplicated DNA
• Purine analogs act on DNA synthesis chromosomes to either side of the parent cell in structures
called “spindles”. The spindles ensure that each new cell gets
a full set of DNA. Spindles are microtubular fibers formed with
B. Pharmacologic Effects
the help of the protein “tubulin”.
Curative combination therapy for childhood acute lymphocytic
leukemia • *Vincristine binds to tubulin, thus preventing the formation
of spindles and cell division.
C. Toxicities
•Thioguanine: myelosuppression (dose-limiting); stomatitis Taxanes
& diarrhea (dose-limiting)

Page 3 of 12
 • Binds with microtubules to arrest mitosis (mitotic Camptothecin Analogs
spindle inhibitor) – enhances tubulin polymerization • neutropenia, with or without thrombocytopenia
(non-functional tubules) diarrhea
• For IV infusion
Epipodophyllotoxins
• 10% excreted in urine; the rest metabolized • leukopenia
• Nausea, vomiting, stomatitis, and diarrhea
Camptothecin Analogs
Hepatotoxicity
• Target the nuclear enzyme topoisomerase I S-phase-
• Diarrhea is most common ADR of topoisomerase II
specific drugs
inhibitors
• Inhibit topoisomerase I (cuts and relegates single
stranded DNA – DNA damage)
Miscellaneous Agents
• Irinotecan: prodrug; metabolized active
topoisomerase I inhibitor • Tyrosine kinase inhibitor: imatinib, dasatinib
• Excretion: Topotecan (renal); Irinotecan (bile and • Growth factor receptor inhibitor: cetuximab, gefitinib,
feces) erlotinib, bavacizumab
• Topotecan: ovarian; lung • Enzyme asparaginase
• Irinotecan: colorectal • Ribonucleotide reductase inhibitor (urea analog),
hydroxyurea
Epipodophyllotoxins
• Retinoic acid derivatives: tretinoin, isotretinoin
• S and G2 phases specific
• Apoptosis inductor (release of cytochrome C): arsenic
• Forms complexes with topoisomerase II resulting in
trioxide
DNA strand breakage & arrest of cells in late S and
• Adrenocortical suppressant: mitotane
early G2 phases (topoisomerase II inhibitors)
• Cytoprotector: amifostine
• 1-10% cross blood-brain barrier
• Bone marrow growth factors: sagramostim, filgrastim
• Etoposide given oral or IV, irritant
• Teniposide for IV route
Biologic Response Modifiers
• Excreted in the urine
• Monoclonal antibody: trastuzumab, rituximab
• Interferons: alpha-2a, alpha-2b
• Interleukins: aldesleukin (IL2), oprelvekin
B. Pharmacologic Effects
• Myeloid & erythroid stimulating factors: erythropoietin,
Vinca Alkaloids
filgrastim, sargamostim
• Important clinical agents for treatment of leukemias,
• Anti-angiogenesis: vascular endothelial derived
lymphomas, solid tumors and testicular cancer
growth factor (VEGF)

Taxanes
Indications of Biologic Agents
• central role in the therapy of ovarian, breast, lung,
• Trastuzumab: breast CA (metastatic)
esophageal, bladder, and head and neck cancer
• Rituximab: non-Hodgkin’s lymphoma
Camptothecin Analogs
• Interferons: CML; melanoma; NHL; multiple myeloma;
• established activity in colorectal, ovarian, and small
hairy cell leukemia; renal cell Ca
cell lung cancer
• Aldesleukin: renal cell CA; melanoma
• Myelosuppression & diarrhea most common adverse
effect • Oprelvekin: prevention of severe thrombocytopenia
after chemotheraphy
Epipodophyllotoxins • Myeloid & erythroid stimulating factors:
• for testicular cancer in combination therapy and small granulocytopenia & anemia
cell carcinoma of the lung • Management of Side Effects
• Extravasation: preventive; stop; antidote (Na
C. Toxicities thiosulfate for mustargens; hyaluronidase for vincas)
Vinca Alkaloids • Nausea & vomiting: serotonin antagonist
• SIADH (ondansetron)
• Numbness and tingling of the extremities and loss of • Oral lesions: cleansing (NSS etc); analgesic (NSAIDs)
deep tendon reflexes • Alopecia: non-pharmacological
• severe constipation or obstipation • Diarrhea: fluids; opioids (loperamide)
• Constipation: bisacodyl; lactulose
Taxanes • Altered nutritional status: supplements; tube feeding;
• Neutropenia TPN
• hypersensitivity, muscle aching, and neuropathy • Pain: NSAIDs; opioids
• Toxicity is primarily in the bone marrow • Myelosuppression: hematopoietic growth factors

Page 4 of 12
Hormone/hormones antagonists
1. Androgen: fluoxymesterone; testosterone
2. Androgen antagonist: flutamide; cyproterone;
finasteride
3. Estrogen: diethylstilbestrol; ethinyl estradiol
4. Estrogen antagonist: tamoxifen
5. Corticosteroids: hydrocortisone; prednisone
6. Progestin: megetrol acetate; medroxyprogesterone;
hydroxyprogesterone
7. Aromatase inhibitor: aminoglutethimede; anastrozole;
letrozole; exemestane
8. Gonadotropin-releasing hormones: leuprolide;
goserelin
9. Peptide-hormone inhibitor: octreotide (sandostatin)
MOA (hormone/hormones antagonists)
1. Androgen: alters pituitary function function or directly
affects neoplastic cells
2. Anti- androgen: inihibits nuclear androgen binding
3. Estrogen: suppresses testosterone production in males &
alters breast cancer cell response to prolactin
4. Estrogen antagonist: competes with estrogen for binding
on the cytosol estrogen receptor protein in the cancer cell
5. Corticosteroids: promotes apoptotic cell death
6. Progestin: acts directly at the level of the malignant cell
receptor to promote differentiation
7. Aromatase inihibitor: decrease estrogen biosyntheses;
inhibits aromatization of androgen to estrogen
8. Gonadotropin releasing hormone: inhibits leutinizing
hormone and FSH
Toxicity (Hormones)
• Flutamide: breast tenderness and swelling, hot flashes,
impotence, loss of libido
• Fluoxymesterone: cholestatic jaundice
• Tamoxifen: hot flashes, osteoporosis
• Progestin: no myelosuppression, menstrual irregularities,
weight gain, fluid retention
• Corticosteroids: immunosuppression
Miscellaneous Agents
• Tyrosine kinase inhibitor: imatinib, dasatinib
• Growth factor receptor inhibitor: cetuximab, gefitinib,
erlotinib, bavacizumab
• Enzyme asparaginase
• Ribonucleotide reductase inhibitor (urea analog),
hydroxyurea
• Retinoic acid derivatives: tretinoin, isotretinoin
• Apoptosis inductor (release of cytochrome C): arsenic
trioxide
• Adrenocortical suppressant: mitotane
• Cytoprotector: amifostine
• Bone marrow growth factors: sagramostim, filgrastim
Biologic Response Modifiers
• Monoclonal antibody: trastuzumab, rituximab
• Interferons: alpha-2a, alpha-2b
• Interleukins: aldesleukin (IL2), oprelvekin
• Myeloid & erythroid stimulating factors: erythropoietin,
filgrastim, sargamostim
• Anti-angiogenesis: vascular endothelial derived growth
factor (VEGF)
Indications of Biologic Agents
• Trastuzumab: breast CA (metastatic)
• Rituximab: non-Hodgkin’s lymphoma
• Interferons: CML; melanoma; NHL; multiple myeloma;
hairy cell leukemia; renal cell Ca
• Aldesleukin: renal cell CA; melanoma
• Oprelvekin: prevention of severe thrombocytopenia after
chemotheraphy
• Myeloid & erythroid stimulating factors: granulocytopenia
& anemia
Management of Side Effects
• Extravasation: preventive; stop; antidote (Na thiosulfate for
mustargens; hyaluronidase for vincas)
• Nausea & vomiting: serotonin antagonist (ondansetron)
• Oral lesions: cleansing (NSS etc); analgesic (NSAIDs)
• Alopecia: non-pharmacological
Page 5 of 12
• Diarrhea: fluids; opioids (loperamide)
Breakthroughs
• Constipation: bisacodyl; lactulose • Some new medicines, called targeted therapies, are
specifically developed to attack a particular target on
• Altered nutritional status: supplements; tube feeding; TPN cancer cells
Ex. Lapatinib for Her2 (+)
• Pain: NSAIDs; opioids

• Myelosuppression: hematopoietic growth factors • Other approaches to targeting drugs more specifically
at the cancer cells – such as attaching drugs to
monoclonal antibodies – may make them more
DRUG COMBINATIONS effective and cause fewer side effects
Ex. Gemtuzumab ozogamicin
Cervix: cisplatin or carboplatin + 5FU
• Chemoprotective agents are being developed to
Colon
protect against specific side effects of certain
1. 5FU + leucovorin + H. interferon + levamisole
chemotherapy drugs. Ex. Dexrazoxane helps
2. Topotecan/irinotecan + 5FU + leucovorin
prevent heart damage
3. 5FU + leucovorin + oxaliplatin
• Some new agents may be given along with
chemotherapy to help overcome drug resistance
Leukemia (ALL)
1. Vincristine + prednisone • Liposomal therapy involves using chemotherapy
2. 6-mercaptopurine + methotrexate + drugs that have been packaged inside liposomes
cyclophosphamide (synthetic fat lobules). Ex. The encapsulated form of
Breast doxorubicin
1. Cyclophosphamide + doxorubicin + 5FU
2. Doxorubicin + cyclophosphamide
3. Cyclophosphamide + methotrexate + 5FU +
prednisone
4. Anastrozole or letrozole/tamoxifen
5. Paclitaxel/docetaxel

Lungs
1. Cisplatin + taxane
2. Non-small cell: navelbine + carboplatin

Leukemia (AML): cytarabine + daunorubicin

Leukemia (CLL): chlorambucil + prednisone
Leukemia (CML): busulfan

Thyroid: I-131 + doxorubicin

Ovary: cisplatin + paclitaxel

Stomach: 5FU + cisplatin

Pancreas: gemcitabine
Non-Hodgkin’s lymphoma: cyclophasphamide + doxorubicin +
vincristine + prednisone

Hodgkin’s: vinblastine, doxorubicin, dacarbazine, bleomycin

Principles of Agent Selection

• Choose individually active drugs
• Choose drugs in which the dose limiting toxicities
differ
• Select agents for a combination for which there is a
biochemical or pharmacologic rationale
• Be cautious when attempting to improve on a
successful 2-drug combination; an intolerable level of
toxicity; unchanged or reduced anti-tumor effect

Page 6 of 12
Alkylating Agents
Drug Phase Mechanism Toxicity Pharmacokinetic Indications Notes
s
Nitrogen Mustards
Non-cell cycle “Bifunctional Bone Marrow Suppression PO. Slow acting Chronic Lymphocytic Leukemia
specific Alkylating Agent’ Ovarian Cancer
Chlorambucil Immunosuppression
(Leukeran) Crosslinks DNA
by binding to both
strands
Non-cell cycle Metabolize to Hemorrhagic cyctitis, PO/IV As a single agent, a daily oral dose of 100 Cystitis can be
specific phospharamide cardiotoxicity, nausea mg/m2 for 14 days has been recommended reduced in intensity
mustard, a DNA as adjuvant therapy for breast cancer, and or prevented by the
alkylating agent Interstitial pneumonitis for patients with lymphomas and chronic parenteral
and fibrosis lymphocytic leukemia coadministration of
Cyclophosphamide mesna and ample
(Cytoxan) Platelet sparing Childhood tumors; solid tumors; bone and fluid intake. Mesna
soft tissue; lymphocytic leukemias, multiple does not negate
Severe N & V myeloma the systemic
antitumor activity of
Organ rejection after transplantation the drug.

Essential component of many effective drug

combinations for non-Hodgkin's lymphomas,
ovarian cancers, and solid tumors in children
Non-cell cycle Alkylated Severe urinary tract and IV In combination for germ cell testicular Adequate hydration
specific metabolites CNS toxicity cancer and is widely used to treat pediatric and
ifosfamide and adult sarcomas coadministration of
damaged DNA Nausea, vomiting, mesna have
Ifosfamide anorexia, leukopenia, Common component of high-dose reduced its bladder
(Ifex) nephrotoxicity, and veno- chemotherapy regimens with bone marrow toxicity
occlusive disease of the or stem cell rescue
liver
Testicular; lung; bone and soft tissue
Platelet sparing sarcomas; lymphoma
Non-cell cycle Binds to N7 of Nausea and vomiting, IV. Rapid uptake, Formerly used primarily in the combination First clinically used
specific guanine lacrimation, and clearance and chemotherapy regimen MOPP nitrogen mustard
myelosuppression action. (mechlorethamine, vincristine [ONCOVIN], and is the most
Mechlorethamine Crosslinks DNA procarbazine, and prednisone) in patients reactive of the
(Mustargen) by binding to both with Hodgkin's disease drugs in this class
strands

Page 7 of 12
Alkylating Agents
Pharmacokinetic
Drug Phase Mechanism Toxicity Indications Notes
s
Ethylenimine
Derivative Non-cell cycle DNA alkylating Myelosuppression, and to IV Primarily for high-dose chemotherapy
specific agent a lesser extent mucositis, regimens
Thiotepa stomatitis and diarrhea
(Thioplex) Bone marrow transplant conditioning
In high-dose, produces
neurotoxic symptoms,
including coma and
seizures
Alkyl Sulfonate
Non-cell cycle Myelosuppressive PO/IV Used in the chronic phase of CML to
Busulfan specific properties, and prolonged suppress granulocyte counts
(Myleran) thrombocytopenia

Pulmonary complication
Triazenes
Non-cell cycle Methylating agent Nausea and vomiting IV. Extravasation In combination regimens for the treatment of
specific after metabolic of the drug may Hodgkin's disease
activation in the Flu-like syndrome cause tissue
liver. Its active consisting of chills, fever, damage and Melanoma and soft tissue sarcomas
Dacarbazine (DTIC) metabolite is a malaise, and myalgias severe pain.
monomethyl
triazeno Myelosuppression, with
metabolite, MTIC, both leukopenia and
and it kills cells in thrombocytopenia
all phases of the
cell cycle.
Platinum Analogs
Non-cell cycle Kills cells in all Nephrotoxicity, IV Major antitumor activity in a broad range of To prevent renal
specific stages of the cell Ototoxicity (tinnitus and solid tumors, including non-small cell and toxicity, it is
Cisplatin cycle, binds DNA high-frequency hearing small cell lung cancer important to
(Leukeran) through the loss) establish a chloride
formation of In combination with bleomycin, etoposide, diuresis by the
intrastrand and Progressive peripheral ifosfamide, or vinblastine cures 90% of infusion of 1-2 L of
*with resistance with interstrand cross- motor and sensory patients with testicular cancer normal saline prior
cisplatin, use links, and inhibits neuropathy to treatment
Oxaliplatin DNA synthesis Sensitizes cells to radiation therapy and
and function Anaphylactic-like enhances control of locally advanced lung,
reactions, characterized esophageal, and head and neck tumors
by facial edema, when given with irradiation
bronchoconstriction,
tachycardia, and

Page 8 of 12
 hypotension

Pharmacokinetic
Alkylating Agents Phase Mechanism Toxicity Indications Notes
s
Drug
Nitrosoureas
Non-cell cycle Inhibits DNA Myelosuppression, long- IV malignant gliomas
Carmustine specific synthesis by DNA term use leads to renal
alkylation and failure brain; lymphomas; multiple myeloma;
protein melanoma
carbamoylation

Antimetabolites
Drug Phase Mechanism Toxicity Pharmacokinetics Indications Notes
Folic Acid Analogs

Methothrexate S phase Inhibits megaloblastic PO at doses of less Critical drug in management of acute Also used in
(MTX) dihydrofolate anemia than 25 mg/m2 lymphoblastic leukemia (ALL) in children treatment of
reductase (DHFR), rheumatoid arthritis
Mucositis, IV for larger doses Of limited value in leukemia seen in adults,
tetrahydrofolate myelosuppression, and except for treatment and prevention of In combination with
(THF) synthesis, thrombocytopenia leukemic meningitis a prostaglandin:
and de novo purine induces abortion
nucleotide Alopecia, dermatitis,
synthesis interstitial pneumonitis,
nephrotoxicity,
defective oogenesis or
spermatogenesis,
abortion, and
teratogenesis
Pyrimidine Analogs

S phase Inhibits thymidine megaloblastic IV (oral absorption Partial responses in 10-20% of patients with
5-Fluorouracil (5- synthase anemia; dose-limiting; erratic) metastatic colon carcinomas, upper GIT
FU) carcinomas, breast carcinomas
myelosuppression;
Incorporation of
stomatitis; hand-foot
FUTP into RNA
results in syndrome (painful
alternation in RNA erythematous In combination with leucovorin: survival
processing and desquamation of advantage for patients with colorectal CA and
mRNA translation palms and soles) gastric CA

Inhibits DNA
synthesis and
function

Page 9 of 12
 Cytidine Analogs

S phase Biotransformed to Myelosuppression IV Most important antimetabolite used in the

Cytarabine (ara-C) active forms that leading to acute, therapy of acute myelocytic leukemia (AML)
then inhibit DNA severe leukopenia,
thrombocytopenia, and
polymerase and anemia
DNA synthesis
GI disturbances,
stomatitis,
conjunctivitis,
reversible hepatic
enzyme elevations,
noncardiogenic
pulmonary edema, and
dermatitis

Cerebellar toxicity
(ataxia and slurred
speech) and cerebral
toxicity (seizures,
dementia, coma)

S phase Inhibits DNA Myelosuppression, IV infusion Important drug for patients with metastatic Gemcitabine is a
synthesis and nausea, fever pancreatic cancer, non-small cell lung very potent
repair, and With short plasma cancer, ovarian, bladder, esophageal, and radiosensitizer and
ribonucleotide half-life of ~15 min head and neck cancer should not be used
Gemcitabine reductase with radiotherapy
Women and elderly except in closely
subjects have monitored clinical
slower clearance trials
Purine Analogs

6-Mercaptopurine S phase Nucleotides formed Myelosuppression, PO; short half-life Acute leukemia
(6-MP) from 6-MP inhibit hepatoxicity
de novo purine
synthesis and also
become
incorporated into
nucleic acids

Inhibits DNA Converted to Myelosuppression, IV Hairy cell leukemia, other

repair (non cladribine thrombocytopenia, leukemias/lymphomas
Cladribine phase triphosphate, and nausea, infections,
specific) and incorporated into high fever, headache,
synthesis (S DNA producing fatigue
phase) DNA strand breaks
*TS – thymidine sythase *FUTP – 5-fluorouridine-5’-triphosphate

Page 10 of 12
Antibiotics
Drug Phase Mechanism Toxicity Pharmacokinetics Indications Notes
Anthracyclines

Doxorubicin Cell Cycle- Cause topo II- Myelosuppression, IV. severe local AIDS-related Kaposi’s sarcoma, malignant
(Adriamycin) Nonspecific dependent DNA leukopenia, vesicant action and lymphomas, adjuvant and metastatic
(CCNS) cleavage & Erythematous tissue necrosis carcinoma of the breast and small cell
streaking near the site
intercalate with carcinoma of the lung
of infusion
DNA double helix;
generation of free Cardio toxicity
radicals

Cell Cycle- cause topo II- Bone marrow IV Primarily used in the treatment of AML Patients should be
Daunorubicin Nonspecific dependent DNA depression, stomatitis, advised that the
(Daunoxome) (CCNS) cleavage & alopecia, GI drug may impart a
intercalate with disturbances red color to the urine
DNA double helix;
generation of free Cardiac toxicity
radicals
Non-anthracyclines

G2-M phase cause DNA strand Pulmonary fibrosis, IV/IM Squamous carcinoma of the cervix, and
Bleomycin scission by little against lymphomas and testicular tumors
interacting with O2 myelosuppression, it
and iron has significant
advantages in
combination with other
cytotoxic drugs,
cutaneous toxicity,
including
hyperpigmentation,
hyperkeratosis,
erythema

Cell Cycle- bifunctional or myelosuppression, IV May be used by direct instillation into the
Nonspecific trifunctional characterized by bladder to treat superficial carcinomas
Mitomycin (CCNS) alkylating agent, marked leukopenia
inhibits DNA and thrombocytopenia In combination with 5-FU, cisplatin, or
synthesis doxorubicin: carcinomas of the cervix,
stomach, breast, bladder, anus, head and
neck, and lung

Natural Products (Mitotic Disrupters)

Drug Phase Mechanism Toxicity Pharmacokinetics Indications Notes
Vinca Alkaloids M-phase Binds tubulin, Leukopenia, GI IV curative therapy of metastatic testicular
Vinblastine specific depolymerizes disturbances including tumors, standard curative regimen for
(Velban) microtubules nausea, vomiting, Hodgkin's disease
anorexia, and diarrhea

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 Vincristine M-phase Binds tubulin, severe neurological IV Hodgkin's disease or non-Hodgkin's
depolymerizes manifestations lymphomas
microtubules
Taxanes
M phase Stabilizes Peripheral IV Metastatic ovarian cancer, breast cancer
Paclitaxel microtubules, neuropathy,
prevents myelosuppression,
depolymerization nausea, myalgias
essential for
mitosis
Epipodophyllotoxins
G1-S phase Interferes with Myelosuppression, IV/PO Testicular and lung cancers
Etoposide topoisomerase nausea, mucositis
causing DNA
strand breaks

Natural Products
Drug Phase Mechanism Toxicity Pharmacokinetics Indications Notes
Camptothecins Cell cycle Interacts with Neutropenia, with or IV CML and in myelodysplastic syndromes
Topotecan -nonspecific topoisomerase I, without
DNA breaks during thrombocytopenia
replication
Cell cycle Interacts with Delayed diarrhea, with IV colorectal cancer
Irinotecan -nonspecific topoisomerase I, or without neutropenia,
DNA breaks during myelosuppression
replication
Hormone/ - competitive vasomotor symptoms PO prevention of breast cancer in high-risk
Hormones inhibitor of (hot flushes), atrophy patients, for the adjuvant therapy of early-
antagonists estradiol binding to of the lining of the stage breast cancer, and for the therapy of
advanced breast cancer
the ER vagina, hair loss,
Anti-estrogen
Tamoxifen nausea, and vomiting

* Texatogenicity: all

* Gonadal: all spermatogenic dysfunction; amenorrhea

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