Hyperplasia
Increased cell size
Unchanged function
Reversible
Metaplasia
Adaptive substitution from one differentiated cell type to another
Protective response
Some loss of function
Dysplasia
Loss of uniformity, loss of architectural orientation
Reversible
Neoplasia
Uncoordinated growth
Decreased response to suppressore genes
Immortilization
Irreversible
Less differentiated, more like stem cells
Grade 1 Tumor
Closely resembles tissue of origin
Retains specialized function
Grade 2 Tumor
Moderately differentiated
Less like tissue of origin
Increased mitosis
Grade 3 Tumor
Poorly differentiated
Tumor doesn't resemble tissue of origin
Increased variation
Increased mitosis
Grade 4 Tumor
Very poorly differentiated
No resemblence to tissue of origin
Highly variable
Enhanced mitosis
Metastatic
Synthetic Antineoplastics
Alkylating agents
Antimetabolites
Natural Antineoplastics
Plant alkaloids
Antibiotics
Biological Response Modifiers
Hormonal Agents
Immunostimulant
Alkylating Agents
Form carbonium ions or transition intermediates
Not cell cycle specific (G1 and S)
Significant bone marrow suppression
CNS mediated N/V
Can cause pulmonary fibrosis
Nitrogen Mustards
Blistering agent when in contact with mucous membrane
Mechlorethamine
MOPP regimine in Hodgkin's Disease
Quick activation, quick inactivation
Treat extravasation with Na Thiosulfate
Cyclophosphamide
N/V, alopecia, cystitis, pulmonary fibrosis, immunosuppression
Use MESNA to treat cystitis
Idosfamide
CYP3A4
Less potent than cyclophosphamide
Neurotoxicity - hallucinations, confusion, depression
Platelet suppression, more nephrotoxicity
Use MESNA to treat cystitis
Chlorambucil
Slow depression of the bone marrow
GI discomfort, seizures, dermatitis
Melphalan
Bone marrow ablation in transplants
Less N/V, no alopecia
Nitrosoureas
Lipophilic (brain tumors)
Increased myeolosuppression, Fibrosis, Renal toxicity
Secondary leukemia very common
Carmustine (BCNU), Lomustine
Dacarbazine
P450 metabolized to Diazomethane
Flu-like syndrome, muscle pain
Infertility
Severe N/V
Procarbazine
P450 metabolized to Diazomethane
Flu-like syndrome, muscle pain
CNS depression
Leukogenic
Immunosuppressant
Temozolomide
P450 metabolized to Diazomethane
Flu-like syndrome, muscle pain
Drug of choice for malignant gliomas
Thiotepa
Converted to TEPA
Cross-links DNA
Ablation of bone marrow
Alopecia, coma, seizures
Busulfan
Acute myelosuppression
Used with cyclophosphamide to ablate bone marrow
Can cause fatal lung damage
Mild nausea
Altretamine
Second line ovarian cancer
Neurotoxicity (Depression, confusion, hallucinations)
Cisplatin
Water activated
Reactis with sulfhydral groups
Sensitizes some tumors to radiation
Severe N/V
Nephrotoxic, Ototoxic
Sulfhydryl rescue - Na Thiosulfate
Carboplatin
Bone marrow ablation
Requires activation, slower, less reactive than Cisplatin
Moderate N/V
Oxaliplatin
Mild N/V
peripheral neuropathy
Anaphylactic shock
Angioedema
Methotrexate
Prevents formation of tetrahydrofolate which limits conversion of dUMP to dTMP
Used for Acute Lymphoblastic Leukemia in children
BBW for hepatic disease, pulmonary disease, infections, pregnancy
5-Flurouracil
fdUMP completes with dUMP to inhbit thymidilate synthase
Inhibits RNA synthesis
Hand-foot syndrome
Floxuridine
Given via hepatic artery for liver cancer and metastatic colon cancer
Capecitabine
Prodrug FUdR
Non-responsive metastatic breast or colorectal cancer
Cytarabine
Cytosine analog where ribose is replaced by D-arabinose
Inhibits DNA polymerase
Most effective for meylogenous leukemia
Moderate N/V/D
Potent myelosuppression
Mercaptopurine
Inhibits Hypoxanthine-guanine phosphoribosyl transferase - inhibits adenosine and xanthine formation
Prevents DNA synthesis and RNA
Allopurinol is given to increase 6MP levels and decrease uric acid levels
Fludarabine
Fluorinated adenosine arabinose
Inhibits DNA polymerase
Cladribine
Inhibits DNA polymerase
N/V, infections
Tioguanine
Thioanalog of guanine
Hematological suppression, bleeding, GI effects
Antimetabolites
Inhibits enzyme or substrate for purines/pyrimidines
Cytotoxic effects durin S phase and impaired nucleoside synthesis in G1 phase
Antibiotics
Not cell cycle specific - do not need to give over several days
Rhabdomyosarcoma and Wilm's tumor
Pancytopenia, N/V/ anorexia
Daunorubicin, Doxorubicin
Inhibits topoisomerase II and DNA polymerase
Cardiotoxic - lifetime dose
Moderate N/V
Discoloration of the urine (red)
Give with Dexrazoxane which chelates free radicals
Bleomycin
Specific for G2 phase
Low myelosuppression
Dry cough which can lead to pulmonary fibrosis
Flu-like syndrome (fever, chills)
Mild N/V
Hyperpigmentation, blistering of skin
Vinca Alkaloids
Block spindle fiber assembly in the M phase
Biliary excretion
Hyperuricemia - give with Allopurinol
Taxanes
Block spindle fiber disassembly in the M phase
Vinblastine
Periwinkle
Mores solid tumors
Dose limitin myelosuppression
Significant N/V/D
Vincristine
Dose limiting neurotoxicity
Peripheral neuropathies of hands and feet
Suppression of deep tendon reflexes
Cranial nerve damage - jaw apin, face palsies
Minimal myelosuppression
Paclitaxol
Myelosuppression
Hand and foot syndrome, myalgia
Docetaxel
Neutropenia
Edema
Etoposimide
Specific for S-G2 phase
Dose limiting myelosuppression
40% excreted unchanged in the urine
Unusual nonlymphocytic leukemia due to chromosome 11
Inhibites topoisomerase I and II
Teniposide
Specific for S-G2 phase
Dose limiting myelosuppression
Extensively metabolized
Inhibites topoisomerase I and II
Irinotecan
Inhibits topoisomerase I
Dose limiting myelosuppression
Metabolized and excreted in bile
Decrease cholinesterase activity
Bad diarrhea
Topetecan
Inhibits topoisomerase I
Dose limiting myelosuppression
renal excretion
Imatinib
Decrease myeloid tyrosine kinases responsible for cell proliferation
Gefitinib
Inhibits epidermal growth factor (ErbB1 or HER1)
Dry skin, rash
Erlotinib
Inhibits HER1 (ErbB1)/EGFR
Diarrhea, rash, elvated liver enzymes
Treats metastatic non-small lung cancer
Lapatinib
Inhibts ErbB1 (HER1) and ErbB2 (HER2)
Treates metastatic breast cancer no longer sesitive to Trastusumab
Bortezomib
Increases IkB and decreases NF-kB
Fatigue
Thrombocytopenia
Neuropathy
Limb pain
Rituximab
Antibody for CD20
Flu-like symptoms
Alematuzumab
Binds to CD52 antigen on T and B cells
Decreases T-cells
Increases opportunistic infections
Tratuzumab
Antibody to human epidermal growth factor 2 (HER2/neu, ErbB2)
Cardiomyopathy
Bevacizumab
Antibody to vascular-endothelia growth factor (VEGF)
Wet macular degeneration
CHF, perforation of the stomach and GI tract
NO LONGER for breast cancer
Gemtuzumab, Ozagamicin
Antibody to CD33 antigen
Tomoxifen
Competes with estrogen for receptor binding
Can by used prophylactically
Hot flashes, myelosuppression
DVT, Pulmonary embolism
Positive effects on bone and cholesterol
Toremifene
increases TNFb to decrease cell proliferation and cell growth
Hot flashes, myelosuppression
DVT, Pulmonary embolism
Raloxifene
reduce the risk of breast cancer in postmenopausal women with osteoperosis and breast cancer
Increased thromboembolism
Hot flashes, Muscle cramps
Teratogenic
Fluvestrant
Selective estrogen receptor down-regulator
Pure anti-estrogen
Nausea, pain
Vasodilation, headache
Anastrozole, Letrozole
Competitive aromates inhibitor - decrease estrogen
All women with postmenopausal estrogen sensitive breast cancer should receive aromatase inhibitors
Hair thinning, Muscle pain, Hot flashes
Exemestane
Irreversible aromatase suicide inhibitor
Women after 2-3 years of Tamoxifen or from 5 years by itself
Edema, fatigue
Less gynecological, more visual and bone problems
Flutamide, Nilutamide, Bicalutamide
Binds androgen receptor to block testosterone stimulation of cancer cells
Usually given with Leuprolide or Goserelin
Gynecomastia, GI distress, Decreased libido, vasomotor flushing
Leuprolide, Goserelin
Analog of GnRH - inhibit release of FSH and LH
Impotence, hot flases, gynecomastia, N/V
Interferon alpha
Increase cytotoxicity of NK cells
Increases phagocytic activity of macrophages
Increase ability of macrophaages to present processed antigen to T-helper cells
Flu-like syndrome
Depression, dizziness
CI in pregnancy
Aldesleukin (IL-2)
Stimulate proliferation and activation of lymphokine-activated killer cells and tumor-infiltrating lymphocytes
Turns on NK cells
Metastatic renal cell carcinoma
Capillary leak syndrome
Pulmonary edema, failure
Hepatotoxicity
Cortisol Binding Affinity
MR > GR
Cortisol Binding Capacity
GR > MR
Glucocorticoid Effects in Kidney
Increase Ca loss
Na retention (increase BP)
May mediate K excretion
ER alpha
Highest in reproductive tract and CV system
ER beta
Highest in ovary and prostate
Synthetic Estrogen: Diethlystillbestrol
Ethinyl Estradiol
Mestranol
Clomiphene (Anti-estrogen)
Synthetic Estrogen Receptor Modulator (SERM)
Tamoxifene - agonist at uterus and bone, antagonist at breast
Raloxifene - agonist at bone, antagonist at uterus and breast
Environmental Estrogens
Plychlorinated biphenyls (DDT)
Plasticisers
Phytoestrogens
Flavones
Synthetic Progestins
Methocyprogesterone acetate -MPA
Megestrol acetate
19-Nortestosterone
Norethindrone
Levonorgesterel
Norestrel
Norestimate
19-Norgesterel
Mifepristin - anti-progestin
Onapristone - anti-progestin
Estrogen action in OC
Blocks FSH secretion and LH surge by negative feedback effect
Estrogen + Progestin actions in OC
Allows uterine/vaginal changes
Monophasic OC
Constant estrogen and progesteron
Biphasic OC
Estradiol, then E + P
Triphasic OC
Constant estrogen, Increasing progesterone
Or estrogen increases mid-cycle, increasing progesterone
Norgestrel, Levonorgestrel
High AR activity
Norethidrone
More PR, less AR activity
Norgestimate
Low AR, little ER activity
Desogestrel
Less AR, no ER
Better HDL
Drospirenone
Anti-MR, anti-AR
Positive Effects of E + P therapy
Reduce incidences of ovarian and endometrial cancer, ovarian cysts, benign fibrocystic breast disease
Decrease LDL and increase HDL
Negative Side effects of +P therapy
Estrogen could cause incease in endometrial cancer
Breast tenderness, edema, headache, anorexia, nausea, changes in libido
Increase risk of hypertension, thrombosis, gall stones
Progestin-Only contraceptives
Norethidrone
Levonorgestrel (Plan B)
MPA (IM)
Progesterone (IUD)
Advantages of Progestin-only contraceptives
Can be used in women who smoke
Disadvantages of Progestin-only contraceptives
Irregular menses
Risk of ectopic pregnancy
MOA of Progestin-only contraceptives
Blunt LH surge
Increase thickness of vervical mucus
Result in thin, atropic endometrium