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ANTICANCER DRUGS IV
PHARMACOLOGY IV
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Natural Product Anticancer Drugs

• The most important of these plant-derived, CCS drugs are:

I. vinca alkaloids (vinblastine, vincristine, vinorelbine)

II. podophyllotoxins (etoposide, teniposide)

III. camptothecins (topotecan, irinotecan)

IV. taxanes (paclitaxel, docetaxel)

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Vinblastine, Vincristine, and Vinorelbine

Mechanisms of action and Resistance
• The vinca alkaloids block the formation of the mitotic spindle by
preventing the assembly of tubulin dimers into microtubules.
• They act primarily in the M phase of the cancer cell cycle.
• Resistance can occur from increased efflux of the drugs from
tumor cells via the membrane drug transporter.
Pharmacokinetics
• These drugs must be given parenterally.
• They penetrate most tissues except the cerebrospinal fluid.
• They are cleared mainly via biliary excretion.
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Vinblastine, Vincristine, and Vinorelbine

Clinical Use
• Vincristine is used in acute leukemias, lymphomas, Wilms'
tumor, and neuroblastoma.
• Vinblastine is used for lymphomas, neuroblastoma,
testicular carcinoma, and Kaposi's sarcoma (tumor caused by
Human herpesvirus 8 ).
• Vinorelbine is used in non-small cell lung cancer and breast
cancer.
Toxicity
• Vinblastine and vinorelbine cause gastrointestinal distress,
alopecia, and bone marrow suppression.
• Vincristine does not cause serious myelosuppression but has
neurotoxic actions and may cause peripheral neuritis.
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Etoposide and Teniposide

Mechanism of action
• Etoposide induces DNA breakage through its inhibition of
topoisomerase II.
• The drug is most active in the late S and early G2 phases of
the cell cycle.
• Teniposide is an analog with very similar pharmacologic
characteristics.
Pharmacokinetics
• Etoposide is well absorbed after oral administration and
distributes to most body tissues.
• Elimination of etoposide is mainly via the kidneys, and dose
reductions should be made in patients with renal impairment.
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Etoposide and Teniposide

Clinical Use
• These agents are used in combination drug regimens for
therapy of lymphoma, and lung, and gastric cancers.

Toxicity
• Etoposide and teniposide are gastrointestinal irritants
and cause alopecia and bone marrow suppression.
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Topotecan and Irinotecan

Mechanisms
• The 2 camptothecins, topotecan and irinotecan , produce DNA
damage by inhibiting topoisomerase I.
• They damage DNA by inhibiting the enzyme that cuts and
relegates single DNA strands during normal DNA repair
processes.
Pharmacokinetics
• Irinotecan is a prodrug that is converted in the liver into an
active metabolite.
• Topotecan is eliminated renally, whereas irinotecan and its
metabolite are eliminated in the bile and feces.
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Topotecan and Irinotecan

Clinical Use
• Topotecan is used for advanced ovarian cancer and for
small cell lung cancer.
• Irinotecan is used for metastatic colorectal cancer.

Toxicity
• Myelosuppression and diarrhea are the most common
toxicities.
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Paclitaxel and Docetaxel

Mechanism of action
• Paclitaxel and docetaxel interfere with the mitotic spindle.
• They act differently from vinca alkaloids, since they prevent
microtubule disassembly into tubulin monomers.

Pharmacokinetics
• Paclitaxel and docetaxel are given intravenously.
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Paclitaxel and Docetaxel

Clinical Use
• The taxanes have activity in a number of solid tumors,
including breast, ovarian, lung, gastroesophageal, prostate,
bladder, and head and neck cancers.
Toxicity
• Paclitaxel causes neutropenia, thrombocytopenia, a high
incidence of peripheral neuropathy, and possible
hypersensitivity reactions during infusion.
• Docetaxel causes neurotoxicity and bone marrow depression.
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Antitumor Antibiotics
• This category of antineoplastic drugs is made up of several
structurally dissimilar microbial products and includes the
anthracyclines, bleomycin, and mitomycin.
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Anthracyclines
Mechanism of action
• The anthracyclines ( doxorubicin , daunorubicin, idarubicin ,
epirubicin , mitoxantrone ) intercalate between base pairs,
inhibit topoisomerase II, and generate free radicals.
• They block the synthesis of RNA and DNA and cause DNA
strand scission.
• Anthracyclines are CCNS drugs.
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Anthracyclines
Pharmacokinetics
• Doxorubicin and daunorubicin must be given intravenously.
• They are metabolized in the liver, and the products are excreted in the
bile and the urine.
Clinical Use
• Doxorubicin is used in Hodgkin's and non-Hodgkin's lymphoma,
myelomas, and breast, lung, ovarian, and thyroid cancers.
• The main use of daunorubicin is in the treatment of acute
leukemias.
• Idarubicin, a newer anthracycline, is approved for use in acute
myelogenous leukemia.
• Epirubicin is used in breast cancer and gastroesophageal cancer.
• Mitoxantrone is used in acute myeloid leukemias, non-Hodgkin's
lymphoma, breast cancer, and gastroesophageal cancer.
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Anthracyclines
Toxicity
• These drugs cause bone marrow suppression,
gastrointestinal distress, and severe alopecia.
• Their most distinctive adverse effect is cardiotoxicity, which
includes initial electrocardiographic abnormalities (with the
possibility of arrhythmias) and slowly developing, dose-
dependent cardiomyopathy and congestive heart failure.
• Dexrazoxane, an inhibitor of iron-mediated free radical
generation, may protect against the dose-dependent form of
cardiotoxicity.
• Liposomal formulations of doxorubicin may be less
cardiotoxic.
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Bleomycin
Mechanisms
• Bleomycin is a mixture of glycopeptides that generates free
radicals, which bind to DNA, cause strand breaks, and inhibit
DNA synthesis.
• Bleomycin is a CCS drug active in the G2 phase of the tumor
cell cycle.
Pharmacokinetics
• Bleomycin must be given parenterally.
• It is inactivated by tissue aminopeptidases, but some renal
clearance of intact drug also occurs.
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Bleomycin
Clinical Use
• Bleomycin is a component of drug regimens for Hodgkin's
lymphoma and testicular cancer.
• It is also used for treatment of lymphomas and for squamous
cell carcinomasa (cancer of a kind of epithelial cell, the squamous cell).
Toxicity
• The toxicity profile of bleomycin includes pulmonary
dysfunction (pneumonitis, fibrosis), which develops slowly and
is dose limiting.
• Hypersensitivity reactions (chills, fever, anaphylaxis) are
common, as are mucocutaneous reactions (alopecia, blister
formation).
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Mitomycin
Mechanisms and Pharmacokinetics
• Mitomycin is a CCNS drug that is metabolized by liver
enzymes to form an alkylating agent that cross-links DNA.
• Mitomycin is given intravenously and is rapidly cleared via
hepatic metabolism.
Clinical Use
• Mitomycin acts is used in combination regimens for
adenocarcinomas of the cervix, stomach, pancreas, and
lung.
Toxicity
• Mitomycin causes severe myelosuppression and is toxic to
the heart, liver, lung, and kidney.
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Miscellaneous Anticancer Agents

Tyrosine Kinase Inhibitors
• It inhibits the tyrosine kinase activity of the protein product of
the bcr-abl oncogene that is commonly expressed in chronic
myelogenous leukemia (CML).
• In addition to its activity in CML, imatinib is effective for
treatment of gastrointestinal stromal tumors.
• Resistance may occur from mutation of the bcr-abl gene.
• Toxicity of imatinib includes diarrhea, myalgia, fluid retention,
and congestive heart failure.
• Dasatinib and nilotinib are newer anticancer kinase inhibitors.
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Growth Factor Receptor Inhibitors:

Trastuzumab
• Trastuzumab , a monoclonal antibody, recognizes a surface
protein in breast cancer cells that overexpress the HER-
2/neu receptor for epidermal growth factor.
• Trastuzumab may cause cardiac dysfunction, including
congestive heart failure.
• The EGFR regulates signaling pathways involved in cellular
proliferation, invasion and metastasis, and angiogenesis
(any formation of new blood vessels).
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Panitumumab
• Panitumumab is a human monoclonal antibody directed
against the EGFR.
• It is approved for refractory metastatic colorectal cancer.
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Bevacizumab
• Bevacizumab is a monoclonal antibody that binds to vascular
endothelial growth factor (VEGF) and prevents it from
interacting with VEGF receptors.
• VEGF plays a critical role in the angiogenesis (formation of new
blood vessels) required for tumor metastasis.
• Bevacizumab has activity in colorectal, breast, non-small cell
lung, and renal cancer.
• Adverse effects include hypertension, infusion reactions,
arterial thrombosis, impaired wound healing,
gastrointestinal perforation, and proteinuria.
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Rituximab
• Rituximab is a monoclonal antibody that binds to a surface
protein in non-Hodgkin's lymphoma cells and induces
complement-mediated lysis, direct cytotoxicity, and
induction of apoptosis.
• It is currently used with conventional anticancer drugs (eg,
cyclophosphamide plus vincristine plus prednisone) in
lymphomas.
• Rituximab is associated with hypersensitivity reactions and
myelosuppression.
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Interferons
• The interferons are endogenous glycoproteins with
antineoplastic, immunosuppressive, and antiviral actions.
• Alpha-interferons are effective against a number of
neoplasms, including hairy cell leukemia, the early stage of
chronic myelogenous leukemia, and T-cell lymphomas.
• Toxic effects of the interferons include myelosuppression and
neurologic dysfunction.
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Asparaginase
• Asparaginase is an enzyme that depletes serum
asparagine;
• it is used in the treatment of T-cell auxotrophic cancers
(leukemia and lymphomas) that require exogenous asparagine
for growth.
• Asparaginase is given intravenously and may cause severe
hypersensitivity reactions, acute pancreatitis, and bleeding.
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Hormonal Anticancer Agents

Glucocorticoids
• Prednisone is the most commonly used glucocorticoid in
cancer chemotherapy and is widely used in combination
therapy for leukemias and lymphomas.
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Gonadal Hormone Antagonists

• Tamoxifen, a selective estrogen receptor modulator, blocks
the binding of estrogen to receptors of estrogen-sensitive
cancer cells in breast tissue.
• The drug is used in the treatment of breast carcinoma and has
been shown to have a preventive effect in women at high risk
for breast cancer.
• Tamoxifen increases the risk of endometrial hyperplasia and
neoplasia.
• Other adverse effects include nausea and vomiting, hot
flushes, vaginal bleeding, and venous thrombosis.
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Gonadal Hormone Antagonists

• Toremifene is a newer estrogen receptor antagonist used in
advanced breast cancer.
• Flutamide is an androgen receptor antagonist used in
prostatic carcinoma .
• Adverse effects include gynecomastia, hot flushes, and hepatic
dysfunction.
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Gonadotropin-Releasing Hormone (GnRH)

Analogs
• Leuprolide, goserelin, and nafarelin are GnRH agonists,
effective in prostatic carcinoma.
• When administered in constant doses so as to maintain stable
blood levels, they inhibit release of pituitary luteinizing
hormone (LH) and follicle-stimulating hormone (FSH).
• Leuprolide may cause bone pain, gynecomastia, hematuria,
impotence, and testicular atrophy.
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Aromatase Inhibitors
• Anastrozole and letrozole inhibit aromatase, the enzyme that
catalyzes the conversion of androstenedione (an
androgenic precursor) to estrone (an estrogenic hormone).
• Both drugs are used in advanced breast cancer.
• Toxicity includes nausea, diarrhea, hot flushes, bone and back
pain, dyspnea, and peripheral edema.
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