Rubicins:  Daunorubicin, Doxorubicin, Epirubicin, Idarubicin

1.  Class

2.  Structrual subclass

3.  MOA

1.  Antitumor antibiotic

2.  Anthracycline

3.  A)  Inhibit topo II; B) high-affinity binding to DNA through intercalation; C) Binding to cell membranes, althering fluidity and transport; D) Generation of semiquinone free radicals and oxygen free radicals that damage DNA

"Relins":  Buserelin, nafarelin, histrelin, deslorelin + Leuprolide

1.  Class

2.  Structural subclass

3.  MOA

1.  Hormonal agents

2.  GnRH receptor agonists

3.  Overstimulate GnRH receptor, stimulating negative feedback, preventing release of gonadal estrogens and androgens

Relix drugs:  Cetrorelix, ganirelix, abarelix, degarelix

1.  Class

2.  Structural subclass

3.  MOA

1.  Hormonal agent

2.  GnRH receptor antagonist

3.  Directly blocks GnRH receptor-mediated release of gonadal estrogens and androgens

Somethign crucial to functioning of that organism/cell, but missing frmo human body and use a drug to disable it

*Problem is that cancer cells are human cells which makes finding something unique difficult

1.  Define malignant

2.  How are they named

1.  Tumor that can result in death and metastasize to other organs

2.  Origin:  carcinoma = epithelial and sarcoma = connective tissue

1.  Tumor that usually does not cause necrosis of neighboring tissue, metastasize to other organs or result in death (although some may mutate to become malignant)

*usually end in -oma (except melanoma and glioma-doesn't metastasize but can cause death)

Most chemo agents kill 99.99% of cacner cells, but the remaining 0.01% may cause recurrence (tumor regrowth or metastasis).  

Toxic effects of chemo mandate lag between treatment so cancer can regenerate.

1.  Debulking

2.  Combo therapy using radiation and other drugs for shorter time b/t tx

1.  Define Cell Cycle Specific Drugs

2.  Define Cell Cycle Nonspecific Drugs

1.  Only target a particular component of cell cycle (mainly G1)

2.  Cell-cycle non-specific drugs can kill in both G0 and cycling cells, although cycling cells more sensitive

1.  Antimetabolites

2.  Antitumor Antibodies

3.  Epipodophyllotoxins

4.  Taxanes

5.  Vinca alkaloids

1.  Alkylating agents

2.  Anthracyclines

3.  Antitumor antibodies

4.  Camptothecins

5.  Platinum analogs

1.  Alkylation of DNA (N7 of G, O6 of G, N1 and 3 of A, N3 of C) blocking replication machinary

2.  Alkylation of cellular proteins by reacting with nucleophiles such as sulfhydrul, amino, hydroxyl, carboxyl, and phosphate groups

*most are bifunctinoal 

Bis(chloro-ethyl)amines

1.  Class of chemo

2.  Members of group (5)

3.  MOA

1.  Alkylating agents

2.  Cyclophosphamide, mechlorethamine (nitrogen mustard), melphalan, chlorambucil, benamustine 

3.  Chloro-ethyl group alkylates N7 of 2 adjacent purines (intrastrand link)

Nitrosoureas

1.  Chemo group

2.  Nitrosoureas (4)

3.  MOA

4.  Special property for difficult to reach tumors

1.  Alkylating agents

2.  Carmustine (BCNU); lomustine, semustien, streptozocin

3.  Alkylate G at N7 primarily, but toxicity is from minor G O6 alkylation causing CG crosslinks inter or intrastrand

4.  Lipid soluble so can pass through BBB to tx brain tumors

Ethyleneimines or Aziridines

1.  Class

2.  Members of group (3)

1.  Alkylating agents

2.  Thiotepa (ovarian cancer), triethylenemelamine, altretamine

Platinum Analogs

1.  Class

2.  Members

3.  MOA

1.  Alkylating agents

2.  Cisplatin; Carboplatin; Oxaliplatin

3.  Form inter and intrastrand DNA cross-links inhibiting DNA synthesis and funciton

Imidazotetrazine derivatives

1.  Class

2.  Members (1)

3.  MOA

1.  Alkylating agents

2.  Temozolomide

3.  Rapid nonenzymatic conversion at physiologic pH to reactive MTIC which alkylates DNA at O6 and N7 positions of Guanine...used for brain cancers

Methylhydrazine Derivative

1.  Class

2.  Member (1)

3.  MOA

1.  Alkylating agents

2.  Procarbazine

3.  Not clear, but may inhibit protein, RNA, and DNA synthesis

Imidazole Carboxamide

1.  Class

2.  Drug (1)

3.  MOA

1.  Alkylating agent

2. Dacarbazine

3.  Hypothesized to be:  A) Inhibition of DNA synthesis by acting as purine analog; B) action as alkylating agent; C) interaction with sulfhydryl groups

Antimetabolites:

1.  Direct MOA

2.  Indirect MOA

1.  Inhibit nucleotide and nucleic acid synthesis by:  inhibiting enzymes involved in DNA replication and/or nucleotide synthesis pathways and/or mimicing nucleotides for incorporation into nucleic acids

2.  Inhibit tumor growth through inhibition of DNA synthesis; inhibit cell maintenance through inhibition of protein synthesis; stimulate apoptosis

DHFR and Thymidylate Synthases (TS)

1.  What does DHFR do?

2.  What it it's product an essential for in the cell?

3.  Role of TS

4.  How do DHFR and TS inhibitors affect cancer cells?

1.  Reduces dihydrofolate to tetrahydrofolate (active folic acid) 

2.  Essential cofactor for de novo thymidine synthesis to make pruine nucleoties, and a portion of the serine/methionine cycle

3.  Transfers methyl from methylene THF onto dUMP to make dTMP

4.  Stop replication directly (TS) or indirectly (DHFR)

Methotrexate

1.  Class

2.  Subclass

3.  MOA

1.  Antimetabolite

2.  Folic acid antagonist

3.  Binds active catalytic site of DHFR competitively (DHF is normal substrate) inhibiting synthesis of THF and stopping DNA, RNA, and protein synthesis

Pemetrexed and Ralititrexed

1.  Class

2. MOA

1.  Antimetabolite

2.  MAIN ACTION: Inhibition of thymidylate synthase (TS) the methyltransferase making dTMP from dUMP

Also target DHFR

Pyrimidine Antagonists

1.  Drugs (4)

1.  5-FU

Capecitabine

Cytarabine

Gemcitabine

5-FU  and Metabolite

1.  Drugs (2)

1.  5-FU and Capecitabine

1.  Deoxyribosyl metabolite (FdUMP):  covalent binding and inhibition of Thymidylate synthase and thymine-less cell death

2.  Deoxyribosyl metabolite (FdUTP):  Inhibits DNA synthesis by incorporating into DNA and inhibiting DNA elongation

3.  Ribosyl metaabolite (FUTP):  Incorporates into RNA to interefere with RNA sythesis and mRNA translation thus inhibiting protein sythesis 

Capecitabine

1.  What is it?

2.  What activates it and why is that good?

1.  Prodrug metabolized to 5-FU

2.  Thymidine phosphorylase which has significantly higher expression in solid tumors than normal cells leading to selective toxicity and reduced myelosuppression, mucositis, N/V

Cytarabine

1.  Class

2.  Subclass

3.  MOA

1.  Antimetabolite

2.  Pyrimidine analog

3.  Inhibits DNA pol alpha and beta (like the purine antagonists fludarabine and cladribine)

Gemcitabine

1.  Class

2.  Subclass

3.  MOA

1.  Antimetabolite

2.  Pyrimidine/deoxycytidine analog

3.  Mimics cytidine and is incorporated into DNA preventing elongation; Inhibits ribonucleotide recductase preventing production of dNTPs for DNA synthesis

Purine Antagonists

1.  Class

2.  Subclass

3.  Drugs (2)

4.  MOA

1.  Antimetabolite

2.  6-thiopurines

3.  6-mercaptopurine (6-MP)

6-thioguanine (6-TG)

4.  Inhibit several enzymes in purine de novo biosynthetic pathway decreasing DNA and RNA synthesis by way of reducing avaible functional purines 

Fludarabine and Cladribine

1.  Class 

2.  Subclass

3.  MOA

1.  Antimetabolite

2.  Purine antagonist

3.  Inhibit DNA polymerase alpha and beta (like pyrimidine antagonist cytarabine)

Vinblastine and Vincristine:

1.  Class

2.  Subclass

3.  MOA

1.  Plant alkaloid

2.  Vinca (periwinkle) alkaloid

3.  Inhibits tubulin polymerization, halting cell cycle and leading to death

*SAme MOA but different clinical spectrum and toxicity profiles

Vinorelbine

1.  Its claim to fame?

Epopodophyllotoxins

1.  Class

2.  Drugs (2) and source

3.  MOA

1.  Plant alkaloids

2.  Etoposide and Teniposide; mayapple root extract derivative of podophyllotoxin

3.  Inhibits topoisomerase II, causing DNA strand breakage leading to cell death

Camptothecins

1.  Class

2.  Drugs (2) and source

3.  MOA

1.  Plant alkaloids

2.  Topotecan and irinotecan; fromt eh camptotheca tree

3.  Inhibit topoisomerase I, preventing cutting and religating of ssDNA leading to cell death

Taxanes

1.  Class

2.  Drugs (2) and source

3.  MOA

1.  Plant alkaloids

2.  Paclitaxel and docetaxel; Pacific and European yew

*docetaxel is semisynthetic

3.  Enhances abnormal microtubule assembly without presence of regulatory proteins and GTP

Antitumor antibiotics

1.  Classes (5)

2.  All derived from what?

1.  Anthracyclines, antracenes,dactinomycin, bleomycin, and mitomycin

2.  Soil microbe Streptomyces

Anthracyclines

1.  Class

2.  Drugs (4)

3.  MOA

1.  Antitumor antibiotics

2.  Doxorubicin, daunorubicin, idarubicin, epirubicin

3.  A)  Inhibit topoisomerase II

B)  Intercalate DNA in major groove blocking replication machinery

C)Binding to cell membranes, altering fluidity and transport

D)  Generation of semiquinone radical through iron-dependent, enzyme-mediated reductive process (can also be caused by estrogen)...cardiotoxicity

Anthracene

1.  Class

2.  Drug (1)

3.  MOA

1.  Antitumor antibiotics

2.  Mitoxantrone

3.  Resemble anthracyclines, bind to DNA to break strands inhibiting DNA and RNA synthesis

Dactinomycin

1.  Class

2.  MOA

1.  Antitumor antibiotic

2.  Intercalating agent b/t adjacent G and C blocking replication machinery

Mitomycin

1.  Class

2.  MOA

1.  Antitumor antibiotic

2.  Alkylating agent that cross-links DNA

Bleomycin

1.  Class

2.  MOA

1.  Antitumor antibody

2.  Small peptide with DNA binding domain at one end and Fe binding domain at the other

Binds DNA and Fe end produces hydroxyl radicals ensuring more DNA damage

Extrogen receptor antagonists

1.  Drugs (2)

2.  General mechanism of action

1.  Tamoxifen and raloxifene

2.  Inhibit estrogen receptor in ER + tumors

Tamoxifen

1.  Class

2.  Subclass

3.  MOA

4.  Tissue response:  Breast, bone, uterus

1.  Hormonal agent

2.  Estrogen-receptor partial agonist

3.  With only partial activation of receptor, overall reduction in activation of receptor

4.  Breast:  Tx breast tumors and prevent recorrence or 2nd primary tumor

Bone:  MAY tx and prevent osteoporosis

Uterus:  Inc risk for 2nd primary uterine cancer

Raloxifene

1.  Class

2.  Subclass

3.  Response in Breast, Bone, Uterus

1.  Hormonal agent

2.  Estrogen-receptor partial agonist

3.  Breast:  tx tumors and prevents recurrence or 2nd primary tumor

Bone:  tx and prevents osteoporosis (remember that tamoxifen is a MAY here)

Uterus:  NO inc risk of 2nd primary uterine cancer

Gonadotropin-releasing hormone agonists and antagonists

1.  MOA

2.  Antagonists (4)

3.  Agonists (5)

1.  bind to GnRH receptors and prevent gonadal release of estrogens and androgens

2.  "relix" drugs:  cetrorelix, ganirelix, abarelix, degarelix

3.  Leprilde and the "Relins" (good band name btw):  buserelin, nafarelin, histrelin, deslorelin

*Initially inc gonadal hormone release but then negative feedback

Aromatase inhibitors 

1.  Class

2.  Drugs (4)

3.  MOA

1.  Hormonal agents

2.  Aminoglutethimide

Anastrozole

Letrozole

Exemestane

3.  Inhibit steroid hormone synthesis

Aminoglutethimide

1.  Class

2.  Subclass

3.  MOA

1.  Hormonal agent

2.  Nonsteroidal corticosteroid synthesis inhibitor

3.  Inhibits conversion of cholesterol to pregnenolone; also inhibits estrone and estradiol synthesis which is loacalized to breast and uterus

Imatinib (Gleevec)

1.  Class

2.  MOA

1.  Misc

2.  Non-competitive Bcr-Abl receptor antagonist

Bcr-Abl is an oncoprotein

Imatinib inactivates the tyr-kinase domain of the receptor preventing substrate phosphorylation

Dasatinib (Sprycel)

1.  Class

2.  MOA

1.  Misc

2.  Nonselective Tyr-kinase receptor antagonist

Epidermal Growth Factor Receptor (EGFR) Inhibtors

1.  Drugs (3)

2.  MOA

1.  Cetuximab (Erbitux), gefitinib (Iressa), erlotinib (Tarceva)

2.  EGFR overexpressed in many tumors so blocking these receptors prevents growth

*Different drugs act on either EGFR 1 or 2 so choice is dictated by tumor

Vacualr endothelial growth factor receptor (VEGF) inhibitors

1.  Drug (1)

2.  MOA

1.  Bevacizumab (Avastin)

2.  VEGF moderates blood supply so blocking this cuts off blood supply to tumor

Asparaginase

1.  Class

2.  Subclass

3.  MOA

1.  Misc

2.  L-asparagine amidohydrolase of bacterial origin

3. Breaks down L-asparagine; tumor cells lack asparagine synthetase so it must import exogenous L-asparagine which the Asparaginase removes

Hydroxyurea

1.  Class

2.  Subclass

3.  MOA

1.  Misc

2.  Urea analog

3.  Inhibits DNA synthesis by inhibiting ribonucleotide reductase (like gemcitabine), preventing production of dNTPs for DNA synthesis

Retinoic Acid Derivatives

1.  Drug (1)

2. MOA

1.  Tretinoin = All trans-retinoic acid

2.  Induces terminal differentiation, preventing proliferation

Arsenic trioxide

1.  Class

2.  MOA

1.  Misc

2.  Induces terminal differentiation, preventing proliferation

1.  Tumors are ____ cell masses

2.  Stages of tumor growth (6)

1.  Heterogenous

2.  Initiation

Promotion

Conversion or transformation

Progression

Local invasion

Metastasis

1.  Different characteristics of different tumor cells often make combination therapy necessary and can result in ____ and/or ____

2.  What 2 things accound for the high failure rate of chemo in advanced cancers?

1.  Lethal tox of chem and/or MDR

2.  A) Heterogenous nature of tumors

B)  Perpetual accumulation

Adjuvant Cancer Therapy

1.  Function

2.  2 types she listed

1.  Systemic tx to prevent micrometastases after local Tx 

2.  Surgery and radiation

Palliative cancer tx

1.  2 goals listed

1.  Shrinking tumors causing blockage or constriction

Relief of bone pain

1.  Provides staging 

2.  Determines how much cancer is there and how far it has spread

1.  Precancerous lesions:  moles or polyps

2.  Removal of organs with things like BRCA mutation or colostomy with MMR mutation

1.  Debulks tumors that cannot be completely removed aiding radiation and chemo

2.  Prolongs life

3.  Provides relief from bloackage, constriction, and pain

1.  To cure or shrink early stage cancer

2.  To prevent metastases

3.  To tx symptoms for advanced cancer

Ionizing radiation

1.  MOA

2.  2 major types and their particles (or waves if you really want to get physics-y)

1.  Forms ions by dislodging electrons as it passes through cell

2.  Photons:  gamma and X-rays (most common)

Particles:  electrons, protons, neutrons, alpha and beta particles

*more energy = better penetration, but also more collateral damage

High-Energy Photon Radiation

1.  Source

1.  Cobalt, cesium, or a linear accelerator

*most common type used today

Electron beam radiation

1.  Source

2.  What type of tumors is it used for?

1.  Linear accelerator

2.  Less penetration so used for surface tumors

Proton radiation therapy

1.  Advantage

1.  Dumps all its energy at end of path in cancer cell so less damage to surrounding tissue

*still newer and needs to be studied in more cancer types

Neutron radiotherapy

1.  Cancers used for 

2.  When used?

3.  Why bad?

1.  Head, neck, prostate

2.  Sometimes helpful when other forms of radiation don't work

3.  Severe long-term side effects so use is limited

External Beam Radiation

1.  MOA

1.  Most widely used today

Linear accelerator focuses beam on tumor, but it also hits normal tissue

Allows large body area to be tx

Internal Radiation Therapy

1.  AKA

2.  MOA

3.  Advantage over External beam radiation

1.  Brachytherapy

2.  Place radioactive container into tumor or cavity close to tumor

3.  Less body exposure, but you can get really high doses in a localized area that would be contraindicated ina  larger area

1.  Define Interstitial Radiation in internal radiation therapy

2.  Define Intracavitary radiation in internal radiation therapy

1.  Radiation source is placed direclty into or next to the tumor using small pellets, seeds, wire, tubes, or containers

2.  Container of radioactive material placed in cavity of the body such as chest, uterus, or vagina

Radiopharmaceuticals

1.  Define

2.  What do you give for bone pain/metastasis (2)

1.  Drugs containing radioactive materials that can be given IV, orally, or into a body cavity

2.  Strontium 89 and samarium 153 b/c they localize in the bone after being given IV

Radiotherapy Thyroid Cancer

1.  Drug of choice

2.  When is it used

3.  Potential long term risks (2)

1.  Radioiodine or Iodine 131

2.  After surgery to destroy any lingering cells that have spread to lymph nodes

3.  Infertility in men, slite increased risk of leukemia

*Women wait 1 year after tx before becoming pregnant

Phosphorous 32

1.  Most common use

2.  Rare uses (2)

1.  Put inside brain tumors that are cystic (hollow) to avoid killing healthy brain

2.  Given IV for polycythemia vera

Peritoneal cavity for ovarian cancer

Radio-labeled antibodies

1.  Advantage

2.  Use

1.  Targeted delivery of radiopharamceuticals

2.  non-Hodgkin lymphomas