The cell cycle
• Has 4 major phases: G1; S; G2; M

– G1 : Interferon

– S: DNA synthesis inhibitors: Fluorouracil; Methotrexate;
Cytarabine; Fludarabine, Mercaptopurine; Thioguanine

– G2: Bleomycin,Etoposide,Teniposide

– M: Mitotic inhibitors: vincristine

All DNA alkylating
drugs and most DNA
intercalating agents

Antitumor antibiotics

• Solid tumors:
        – Initial growth rate is rapid.

• Growth rate decreases as tumor size increases.

       – Surgery and radiation therapy decreases tumor
burden promotes remaining cells to enter the
proliferative phase.

• Growth rate may increase following angiogenesis

• Lymphomas and leukemia: most responsive to
treatment

• Colorectal cancer, lung squamous cell carcinoma are
least responsive to treatment

• Reduce drug uptake
– Methotrexate
• Increase drug efflux
– P-glycoprotein, a pump confer multi drug
resistance.
– Resistance cells have a greater number of
P-glycoprotein

– Dexrazoxane prevent doxorubicin induced
cardiotoxicity
– Administration of mannitol and sodium thiosulfate
prevent cisplatin induced renal toxicity.
   • Mannitol maintain renal blood flow & tubular function
  • Sodium thiosulfate inactivates the drug in the kidney.

– Folinic acid (leucovorin) counteracts methotrexate
induced megalobastic anemia.
– Human granulocyte colony-stimulating factor partially
reverse neutropenia associated with cancer treatment.

• Nitrogen mustards
– Cyclophosphamide; Ifosfamide
– Chlorambucil; Mechlorethamine; Melphalan
• Nitrosureas
– Carmustine; lomustine
• Platinum compounds
– Cisplatin, Carboplatin, Oxaliplatin
• Others:
– Busulfan; Mitomycin; Dacarbazine

• Non Phase Specific agents
• Highly reactive agents. Interacts (cross-link) with
DNA strands
      • Radical formations, Covalent bonds
– Monofunctional agents
• Alkylating agents binding to one site
– result in miscoding of DNA
– Bifunctional agents
• Alkylating agents binding to two sites, cross-linkage of
DNA strains; especially injurious
– Result- inhibition of DNA replication, often cell
death

• Resistance
 – Production of enzymes that repair DNA
 – Decrease uptake of drug
 – Increase production of glutathiones
• Toxicity: Very toxic to dividing cells
  – Bone marrow; hair follicles, GI & germinal
epithelium
  – Blood dycrasia (neutropenia; thrombocytopenia,
anemia)

DNA Alkylating Agent

   -Nitrogen mustards
         – Cyclophosphamide

• Prodrug require metabolic activation (Cyto P450)
• Widely used
– Chronic lymphocytic leukemia; breast & ovarian cancer;
etc
• Potent immunosuppressant
– Rheumatoid arthritis & autoimmune nephritis
• Adverse effects
– Alopecia; nausea & vomiting; myelosuppression;
hemorrhagic cystits
– Cardiac dysfunction; altered ADH secretion

– IV as 1st line for testicular, ovarian and bladder cancer
– Main agent in cancer drug cocktails (including H&N
cancers)
– Useful for treatment of melanoma

• Adverse effects
– GI distress, Alopecia; myelosuppression
– Severe nausea & vomiting and renal toxicity
– Neurotoxic and hematoxicity
– Oxaliplatin: parathesia of the hand, feet, perioral
area, jaw tightness, larynopharyngeal dysesthesia

– Folate Analogs/Antagonists
       • Methotrexate; trimetrexate
       • Premetrexed disodium
– Purine Antagonists
       • Mercaptopurine; thioguanine
– Pyrimidine Antagonists
       • Fluorouracil; Cytarabine
– Ribonucleotide reductase Inhibitors
       • Hydroxyurea

• Methotrexate; trimetrexate
• Premetrexed disodium

• Mercaptopurine; thioguanine

• Fluorouracil; Cytarabine

• Hydroxyurea

– Folic acid analog
• Actively transported into cells
– Mechanism of action
• Substrate for and inhibitor of dihydrofolate
reductase
• i.e. inhibit production of tetrahydrofolic acid
(FH4),leading to a decrease synthesis of
thymidylate, purine nucleotides, and amino
acids……. interferes with nucleic acid and protein
synthesis.
• S phase specific

• Given orally or parenterally
• Do not penetrate the CNS
       – For treating CNS conditions, need to be injected
intrathecally
• Not metabolized, clearance is dependent on renal function.
       – Required adequate hydration to prevent crystallization

• Acute leukemias, non-Hodgkin’s lymphoma; breast cancer,cutaneous T cell lymphoma, etc

• Rheumatoid arthritis; lupus erythematosus; abortifacient

Leucovorin

• “Leucovorin Rescue”
– Leucovorin, given to patients to bypass the
metabolic block
– Usually when methotrexate is given a high dose
(toxic dose)

Pemetrexed disodium (Alimta®)

(Folate Analogs/Antagonists)
• Mechanism:

– Disrupts multiple enzyme targets
• thymidylate synthase (TS), dihydrofolate reductase
(DHFR), glycinamide ribonucleotide formyltransferase
(GARFT), and aminoimidazole carboxamide
ribonucleotide formyltransferase (AICARFT), the
enzymes involved in folate metabolism and DNA
synthesis, resulting in inhibition of purine and
thymidine nucleotide and protein synthesis

– Mercaptopurine and Thioguanine
• Affect the incorporation of purine derivatives into
nucleic acids. The analogues interferes with the
conversionof inosinic acid to nucleotides of adenine
and guanine, resulting in the inhibition of DNA and
RNA synthesis.
– Fludarabine
• Analogue of adenosine, inhibits ribonuclleotide
reductase and DNA polymerase, resulting in the
inhibition of DNA synthesis

– Uses
• Acute & chronic lymphocytic leukemia.
– Toxicity
• Mild myelosuppression, bone marrow suppression
– Drug interaction with
• Allopurinol, reduce dose of mercaptopurine

• Cytarabine
– Cytosine arabinoside or ara-C
• 5-Fluorouracil

• Analogue of thymine
• Prodrug: Required metabolic activation.
– 5-FU: Two active metabolites
           • 5-FdUMP - inhibits thymidylate synthases
            [thymine synthesis - a major building block for
            DNA synthesis]. “ Thymineless death”
           • 5-FdUTP is incoorporated into RNA by RNA
            polymerase and interferes with RNA function

Fluorouracil (Adrucil)

• Toxicity:

Ribonucleotide reductase Inhibitors

– Interfere with synthesis of DNA, during the S
phase of cell division, without interfering with
RNA synthesis
– Inhibits ribonucleoside diphosphate reductase,
preventing conversion of ribonucleotides to
deoxyribonucleotides
– Cell-cycle specific for the S phase and may hold
other cells in the G1 phase of the cell cycle

• Anthracyclines
– These are DNA Intercalating Drugs
        • Daunorubicin; Doxorubicin; Idarubicin (semi-synthetic)
        • Mitoxantrone
– Others
• Bleomycin;
• Dactinomycin

NON PHASE SPECIFIC

• Intercalation of DNA
– Cause deformation and uncoiling of DNA
• Inhibition of topoisomerase II
– Resulting in strain breakage
• Formation of free radicals
– Reactive hydroxyl radicals causing DNA cleavage

• Daunorubicin; Doxorubicin;Idarubicin

– Drug Interactions

Antitumor Antibiotic

– Mixture of two glyco peptides obtained from
Streptomyces verticillis.
– greatest effect on cells in G2 phase, Phase specific

Bleomycin

Mechanism

– Mechanism
• General free radicals, which binds to DNA, cause
strand break and inhibit DNA synthesis.
• and intercalation with DNA

Bleomycin

• Serious: pulmonary and mucocutaneous toxicities
      – Develop pneumonitis that progresses to interstitial
fibrosis, hypoxia and death
    » Monitor patient for cough, dyspnea, pulmonary infiltrates

– Mucocutaneous: oral stomatitis; skin
pigmentation, erythema and edema

• Vinca Alkaloids
    – Vincristine; Vinblastine
    – Vinorelbine is a semisyntehtic derivative of
vincristine
• Taxanes (bark of the western Pacific Yew
tree)
    – Paclitaxel
    – Docetaxel

– Acts on the M phase
    • Prevents cell division
    • Blocks mitosis by disrupting the assembly of
microtubules, the filaments that move chromosomes

– Toxicity

    • GI distress, alopecia, bone marrow depression,
neurotoxic

Vinca Alkaloids

– Adverse effects

Mitotic Inhibitors

• Taxanes

– Paclitaxel [Taxol]; Docetaxel [Taxotere]
– Mechanism

• Late G2
– promote formation of stable microtubule bundle,
thereby inhibiting cell division

• M phase
– disrupting the assembly of microtubules,
inhibiting mitosis

• Alkaloid from Camptotheca acuminata
• Irinotecan; Topotecan

– Inhibit topoisomerase I enzymes
• Prevents repair of DNA stands, impairs
DNA replication; G2 phase

– Toxicity:
• Bone marrow depression; alopecia; peripheral
neuropathy; mucositis
• Nausea, vomiting, diarrhea

– Inhibit topoisomerase II enzymes
• Prevents resealing of DNA stands
• G2 phase

– Toxicity:
• Bone marrow depression; alopecia; peripheral
neuropathy; mucositis
• Nausea, vomiting, diarrhea

• Prednisone is an inactive prodrug
– Metabolized to prednisolone …….. binds to the
intracellular receptor.

– Drug-receptor complex enters the nucleus É
binds to chromatin, activating the transcription of
specific genes …… protein synthesis of proteins.
affinity.

Advance prostate carcinoma

Post Menopausal breast cancers

• Drug Class: SERM (Selective estrogen
receptor modulator)

– Blocks estrogen receptors
       • Tamoxifen (Nolvadex; Soltamox); toremifene
(Fareston); raloxifene
       • Indicated for breast cancer that is estrogen dependent.

-Aromatase inhibitor

– Inhibits both adrenal and extra-adrenal synthesis of
estrone and estradiol
– Fat tissue is major source estrogen
– It also inhibits hydrocortisone synthesis .. leading a
compensatory increases in adrenocorticotropic hormne
(ACTH) to overwhelm the blockage of the adrenal.
Hydrocortisone is coadministered to prevent
symptoms of adrenal insufficiency.

– Flutamide (Eulexin), nilutamide (Nilandron)
bicalutamide (Casodex)

– Indicated for prostate cancer that is androgen
dependent.

– Adverse effects:
• Gynecomastia, hot flashes, breast tenderness, galactorrhea,
impotence, libido decreased, tumor flare; GI distress

– Drug Interaction:
• Warfarin, compete with plasma protein binding sites

_________, primary stimulus
for the secretion of testosterone by the testis

 ________,
stimulate the secretion of estrogen.

Leuteinizing hormone (LH)

Follicle stimulating hormone (FSH)

– Synthetic peptide analogs GnRH

– Agonists, binding with the GnRH receptor in the
pituitary, desensitizing the receptor …….
inhibiting release of FSH and LH
• BOTH androgen and estrogen production are
suppressed.
– Adverse effects
• Hot flushes, impotence, gynecomastia.

• Diethylstilbestrol, leuprolide (leuprorelin)

– Suppress luteinizing hormone from the pituitary
gland, thereby suppress testosterone production
– Estrogen also act directly to suppress prostate
cancer proliferation

Trastuzumab; Rituximab; Bevacizumab;
Cetuximab; Daclizumab; Palivizumab;
Gemtuzumab; I131-tositumomab,
Muromonab,

– mab: monoclonal antibodies
– xi: chimeric antibodies
– Muro: murine antibodies

Bevacizumab  [Avastin]

Adverse effects

Cetuximab [Avastin]

– Adverse effects:

– Target endothelial cell functions
– Vascular endothelial growth factors receptors (VEGFRs)
– Monoclonal antibodies vascular endothelial growth
factors (VEGFs)

Risk of post-operative bleeding when platelet counts
is below _________ /mm3 .

– Benzydamine (Topical)
    • anti-inflammatory, analgesic, antimicrobial (some)
– Topical analgesics
    • Vicious lidocaine, benzocaine, diphenyhydramine
formulated for topical applications.
        – Kaopetate, sulcrafate, milk of magnesia
– Systemic analgesics
    • Opioids, nonopioids, analgesic adjuvants

Minimizes radiation damage

– prevents oxygen radical damages
– few clinical data, evidence is weak

Minimize radiation damage

– Muscarinic receptor agonist
– few clinical data, evidence is suggestive
but weak