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Cancer Chemotherapy

Cell Cycle

Cell Cycle Specific Agents Antimetabolites

Cell Cycle Non-Specific Agents Alkylating Agents Antibiotics Cisplatin Nitrosoureas


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Bleomycin
Podophyllin Alkaloids Plant Alkaloids

Resistance to Cytotoxic Drugs


Increased expression of MDR-1 gene for a cell surface glycoprotein, P-glycoprotein MDR-1 gene is involved with drug efflux Drugs that reverse multidrug resistance include verapamil, quinidine, and cyclosporine MDR increases resistance to natural drug products including the anthracyclines, vinca alkaloids, and epipodophyllotoxins
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Schematic of P-glycoprotein

Alkylating Agents
Nitrogen Mustards Ethylenimines Alkyl Sulfonates Nitrosoureas

Cyclophosphamide

Thiotepa

Busulfan

Carmustine

Legend
Drug Class Sub-class Prototype Drug 6

Alkylating Agents
Mechanism of Action

Alkylate within DNA at the N7 position of guanine Resulting in miscoding through abnormal base-pairing with thymine or in depurination by excision of guanine residues, leading to strand breakage DNA has purine adenine , guanin and pyrimidine as thymine and cytosine Cross-linking of DNA and ring cleavage may also occur

Nitrogen Mustards
Cyclophosphamide Ifosfamide Mechlorethamine Melphalan Chlorambucil

Nitrosoureas
Carmustine Lomustine Semustine Streptozocin-naturally occuring sugar containing

M.O.A.- cross-link through alkylation of DNA All cross the blood brain barrier

Alkylating-Related Agents
Procarbazine Dacarbazine Altretamine Cisplatin Carboplatin

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Platinum Coordination Complexes

These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity. To counteract the effects of nephrotoxicity, give mannitol as an osmotic diuretic, or induce chloride diuresis with 0.1% NaCl.
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Alkylating Agents Toxicity

Bone marrow depression, with leukopenia and thrombocytopenia Cyclophosphamide/Ifosfamide - hemorrhagic cystitis
Reduced

by coadministration with MESNA reduced by chloride diuresis and hydration


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Cisplatin/Carboplatin - ototoxic and nephrotoxic


Nephrotoxicity

Alkylating Agents Therapeutic Uses

Used to treat a wide variety of hematologic and solid tumors Thiotepa ovarian cancer Busulfan chronic myeloid leukemia Nitrosoureas - brain tumors Streptozocin insulin-secreting islet cell carcinoma of the pancreas

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Antimetabolites
Folic Acid Analogs
Methotrexate

Purine Analogs
Mercaptoguanine

Pyrimidine Analogs
Fluorouracil

Legend Drug Class Sub-class Prototype Drug


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Folic Acid Analogs


Methotrexate Trimetrexate Pemetrexed

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Folate
An essential dietary factor, from which THF cofactors are formed which provide single carbon groups for the synthesis of precursors of DNA and RNA To function as a cofactor folate must be reduced by Dihydrofolate reductase to THF

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Methotrexate
Mechanism of Action

The enzyme DHFR is the 1 site of action MTX prevents the formation of THF, causing an intracellular deficiency of folate coenzymes and accumulation of the toxic inhibitory substrate, DHF polyglutamate The one carbon transfer reactions for purine and thymidylate synthesis cease, interrupting DNA and RNA synthesis

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Methotrexate
Mechanism of Resistance
1.
2. 3. 4.

Decreased drug transport Altered DHFR Decreased polyglutamate formation Increased levels of DHFR

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Methotrexate
Therapeutic Uses

Methotrexate- psoriasis, rheumatoid arthritis, acute lymphoblastic leukemia, meningeal leukemia, choriocarcinoma, osteosarcoma, mycosis fungoides, Burkitts and non-Hodgkins lymphomas, cancers of the breast, head and neck, ovary, and bladder
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Trimetrexate
Therapeutic Uses

Trimetrexate- Pneumocystis carinii pneumonia, metastatic colorectal carcinoma, head and neck carcinoma, pancreatic carcinoma, non-small cell carcinoma of the lung

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Pemetrexed
Therapeutic Uses

Pemetrexed- Mesothelioma

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Methotrexate
Toxicity

Bone marrow suppression


Rescue

with leucovorin (folinic acid)

Nephrotoxic

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Purine Antagonists
Mercaptopurine Thioguanine Fludarabine Phosphate Cladribine

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Mercaptopurine/Thioguanine
Must metabolized by Hypoxanthineguanine phosphoribosyltransferase(HGPRT) to the nucleotide form This form inhibits numerous enzymes of purine nucleotide interconversion

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Fludarabine Phosphate
M.O.A.- phosphorylated intracellularly by deoxycytidine kinase to the triphosphate form The metabolite inhibits DNA polymerase- and ribonucleotide reductase Induces apoptosis Tx- non-Hodgkins lymphoma and chronic lymphocytic leukemia

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Cladribine
M.O.A. -phosphorylated by deoxycytidine kinase and is incorporated into DNA Causes DNA strand breaks Tx- hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkins lymphoma

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Pyrimidine Antagonists
Fluorouracil - S-phase Cytarabine Gemcitabine Capecitabine

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Mechanism of Action 5-FU

5-FU is a commonly used pyrimidine antagonist. Like the other pyrimidine antagonists, 5-FU is similar in structure to the normal molecule. It functions to inhibit DNA synthesis both by blocking the formation of normal pyrimidine nucleotides via enzyme inhibition and by interfering with DNA synthesis after incorporation into a growing DNA molecule.

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Therapeutic Uses of 5-FU


Metastatic carcinomas of the breast and the GI tract hepatoma carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areas Combined with levamisole for Tx of colon cancer

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Gemcitabine
Gemcitabine is S-phase specific it is a deoxycytidine antimetabolite it undergoes intracellular conversion to gemcitabine monophosphate via the enzyme deoxycytidine kinase it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine triphosphate

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Gemcitabine
Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA strands do to an addition of a base pair before DNA polymerase is stopped, Gemcitabine inhibits both DNA replication and repair Gemcitabine-induced cell death has characteristics of apoptosis

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Gemcitabine Therapeutic Uses


Gemcitabine treats a variety of solid tumors very effective in the treatment of pancreatic cancer small cell lung cancer carcinoma of the bladder, breast, kidney, ovary, and head and neck

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Plant Alkaloids
Vinca Alkaloids
Vinblastine

Podophyllotoxins
Etoposide

Camptothecins
Topotecan

Taxanes
Paclitaxel

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Vinca Alkaloids

Vinblastine Vincristine Vinorelbine

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Vinca Alkaloids
Mechanism of Action

It does this by inhibiting the formation of spindle fibers. Spindle fibers are responsible the alignment of chromosomes and the separation of the chromosomes in anaphase. Vinblastine blocks the tubulin monomers from forming microtubules. Without proper microtubule formation cell division is not possible. Like all of the vinca alkaloids, this drug also affects cell division in normal cells, explaining 35 many of the side effects seen

Vinblastine
Toxicity
Nausea Vomiting Marrow depression Alopecia

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Vinblastine
Therapeutic Uses

Systemic Hodgkins disease Lymphomas

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Vincristine
Toxicity
Muscle weakness Peripheral neuritis

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Vincristine
Therapeutic Uses

With prednisone for remission of Acute Leukemia

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Vinorelbine
Toxicity

Granulocytopenia

Therapeutic Uses

non-small cell lung cancer

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Podophyllotoxins

Etoposide (VP-16) Teniposide (VM-26)

Semi-synthetic derivatives of podophyllotoxin extracted 41 from the root of the mayapple

Podophyllotoxins
Mechanism of Action

Blocks cells in the late S-G2 phase of the cell cycle through inhibition of topoisomerase II Resulting in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme

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Podophyllotoxins Toxicity

Nausea Vomiting Alopecia Hematopoietic and lymphoid toxicity

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Podophyllotoxins
Therapeutic Uses

Monocytic Leukemia Testicular cancer Oat cell carcinoma of the lung

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Camptothecins

Topotecan Irinotecan

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Camptothecins
Mechanism of Action

Interfere with the activity of Topoisomerase I Resulting in DNA damage

Irinotecan- a prodrug that is metabolized to an active Top I inhibitor, SN-38

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Camptothecins Toxicity

Topotecan
Neutropenia,

thrombocytopenia, anemia

Irinotecan
Severe

diarrhea, myelosuppression

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Camptothecins
Therapeutic Uses

Topotecan- metastatic ovarian cancer (cisplatin-resistant) Irinotecan- colon and rectal cancer

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Taxanes
Paclitaxel (Taxol) Docetaxel

Alkaloid esters derived from the Western and European Yew

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Taxanes
Mechanism of Action

Mitotic spindle poison through the enhancement of tubulin polymerization


In normal cell growth, microtubules are formed when a cell starts dividing. Once the cell stops dividing, the microtubules are broken down or destroyed. Taxanes stop the microtubules from breaking down; cancer cells become so clogged with microtubules that they cannot grow and divide 50

Taxanes
Toxicity

Paclitaxel
Neutropenia,

thrombocytopenia Peripheral neuropathy

Docetaxel
Bone

marrow suppression Neurotoxicity Fluid retention


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Taxanes
Therapeutic Uses Paclitaxel- ovarian and advanced breast cancer Docetaxel- advanced breast cancer

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Antibiotics
Anthracyclines- Doxorubicin & Daunorubicin Dactinomycin Plicamycin Mitomycin Bleomycin

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Anthracyclines
Doxorubicin Daunorubicin

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Anthracyclines
Mechanism of Action

High-affinity binding to DNA through, resulting in blockade of DNA and RNA synthesis DNA strand scission via effects on Top II Binding to membranes altering fluidity Generation of the semiquinone free radical and oxygen radicals

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Anthracyclines
Toxicity Bone marrow depression Total alopecia Cardiac toxicity

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Anthracyclines
Therapeutic Uses

Doxorubicin- carcinomas of the breast, endometrium, ovary, testicle, thyroid, and lung, Ewings sarcoma, and osteosarcoma Daunorubicin- acute leukemia

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Dactinomycin
Mechanism of Action Binds to double stranded DNA through intercalation between adjacent guaninecytosine base pairs Inhibits all forms of DNA-dependent RNA synthesis

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Dactinomycin
Toxicity

Bone marrow depression Oral ulcers Skin eruptions Immunosuppression

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Dactinomycin
Therapeutic Uses Wilms tumors Gestational choriocarinoma with MTX

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Plicamycin
Mechanism of Action Binds to DNA through an antibiotic-Mg2+ complex This interaction interrupts DNA-directed RNA synthesis

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Plicamycin
Toxicity
Hypocalcemia Bleeding disorders Liver toxicity

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Plicamycin
Therapeutic Uses
Testicular cancer Hypercalcemia

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Mitomycin
Mechanism of Action

Bioreductive alkylating agent that undergoes metabolic reductive activation through an enzyme-mediated reduction to generate an alkylating agent that crosslinks DNA

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Mitomycin
Toxicity
Severe myelosuppression Renal toxicity Interstitial pneumonitis

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Mitomycin
Therapeutic Uses
Squamous cell carcinoma of the cervix Adenocarcinomas of the stomach, pancreas, and lung 2nd line in metastatic colon cancer

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Bleomycin
Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations CCS drug that causes accumulation of cells in G2

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Bleomycin
Toxicity
Lethal anaphylactoid reactions Blistering Pulmonary fibrosis

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Bleomycin
Therapeutic Uses
Testicular cancer Squamous cell carcinomas of the head and neck, cervix, skin, penis, and rectum Lymphomas Intracavitary therapy in ovarian and breast cancers

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Hormonal Agents
Estrogen & Androgen Inhibitors Gonadotropin-Releasing Aromatase Inhibitors Hormone Agonists

Tamoxifen

Leuprolide

Aminogluthethimide

Legend Drug Class Sub-class Prototype Drug


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The sex hormones are used in cancer of the female and male breast, prostate, and cancer of the endometrium of the uterus In prostate cancer, estrogens lead to suppression of androgen production All of these agents can produce fluid retention through their sodiumretaining effects Prolonged use of the androgens and estrogens will cause masculinization and feminization, respectively Extended use of adrenocortical steroids can cause HTN, diabetes, and cushingoid appearance

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Anti-Estrogens
Tamoxifen (SERMs) Raloxifene (SERMs) Faslodex

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Tamoxifen

Selective estrogen receptor modulator (SERM), have both estrogenic and antiestrogenic effects on various tissues Binds to estrogen receptors (ER) and induces conformational changes in the receptor Has antiestrogenic effects on breast tissue. The ability to produce both estrogenic and antiestrogenic affects is most likely due to the interaction with other coactivators or corepressors in the tissue and the binding with different estrogen receptors, ER and ER Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes is blocked or altered Resulting in decreased estrogen response. Most of tamoxifens affects occur in the G1 phase of the cell cycle
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Tamoxifen
Toxicity Hot flashes Fluid retention nausea

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Tamoxifen
Therapeutic Uses

Tamoxifen can be used as primary therapy for metastatic breast cancer in both men and postmenopausal women Patients with estrogen-receptor (ER) positive tumors are more likely to respond to tamoxifen therapy, while the use of tamoxifen in women with ER negative tumors is still investigational
When used prophylatically, tamoxifen has been shown to decrease the incidence of breast cancer in women who are at high risk for 75 developing the disease

Anti-Androgen

Flutamide
Antagonizes

androgenic effects approved for the treatment of prostate cancer

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Gonadotropoin-Releasing Hormone Agonists


Leuprolide Goserelin

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Gonadotropoin-Releasing Hormone Agonist


Mechanism of Action Agents act as GnRH agonist, with paradoxic effects on the pituitary Initially stimulating the release of FSH and LH, followed by inhibition of the release of these hormones Resulting in reduced testicular androgen synthesis

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Gonadotropoin-Releasing Hormone Agonist


Toxicity Gynecomastia Edema thromboembolism

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Gonadotropoin-Releasing Hormone Agonist


Therapeutic Uses

Metastatic carcinoma of the prostate

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Aromatase Inhibitors
Aminogluthethimide Anastrozole

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Aminogluthethimide
Mechanism of Action

Inhibitor of adrenal steroid synthesis at the first step, conversion of cholesterol of pregnenolone Inhibits the extra-adrenal synthesis of estrone and estradiol Inhibits the enzyme aromatase that converts androstenedione to estrone

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Aminogluthethimide
Toxicity

Dizziness Lethargy Visual blurring Rash Therapeutic Uses

ER- and PR-positive metastatic breast cancer

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Anastrozole
A new selective nonsteroidal inhibitor of aromatase Treats advanced estrogen and progesterone receptor positive breast cancer that is no longer responsive to tamoxifen

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Miscellaneous AntiCancer Agents


Asparaginase Hydroxurea Mitoxantrone Mitotane Retinoic Acid Derivatives Amifostine

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Asparaginase
An enzyme isolated from bacteria Causes catabolic depletion of serum asparagine to aspartic acid and ammonia Resulting in reduced blood glutamine levels and inhibition of protein synthesis Neoplastic cells require external source of asparagine Treats childhood acute leukemia Can cause anaphylactic shock

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Hydroxyurea
An analog of urea Inhibits the enzyme ribonucleotide reductase Resulting in the depletion of deoxynucleoside triphosphate pools Thereby inhibiting DNA synthesis S-phase specific agent Treats melanoma and chronic myelogenous leukemia

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Mitoxantrone
Structure resembles the anthracyclines Binds to DNA to produce strand breakage Inhibits DNA and RNA synthesis Treats pediatric and adult acute myelogenous leukemia, non-Hodgkins lymphomas, and breast cancer Causes cardiac toxicity

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Mechanisms & Actions of Useful Chemotherapeutic Drugs in Neoplastic Disease

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