Erythropoietin, Epoetin, Epogen

glycoprotein hormone,

produced naturally in kidney(90%) & liver(10%)

Used for: Anemias (NOT TO USE in erythroid-base cancer)

Mechanism: controls RBC production, cytokine for RBC production in bone marrow

Filgrastam

produced naturally by immune cells

stimulates the production of neutrophiles

NO USE in leukemias

Sargramostim, Leukine

produced by activated T-Cells, B-Cells, mast cells, & macrophages

stimulates production of monocytes and granulocytes

G-CSF

NO USE in leukemias

stimulates the production of neutrophiles

Sargramostim 

Leukine

GM-CSF

stimulates the production of monocytes and granulocytes

Alkylating Agent

(Nitrogen Mustard)

mechanism: irreversible DNA changes

(including in cross-linking)

Also changes in RNA and proteins

important side effects: Mutagenic, Teratogenic, carcinogenic

cytotoxic.

Drug: Cyclophosphamide (nitrogen mustard)

Mechanism:inhibit cell division by reacting with DNA

Anti-Metabolite

mechanism:  folic acid analog, inhibits dihydrofolate reductase, slows DNA/RNA synthesis, inhibits protein synthesis

Methotrexate, Thiopurines (mercaptopurine, azathioprine, 6-thioguanine), Fluorouracil

mechanism:  inhibit metabolite use, resulting in halting of cell division or cell growth

Anti-Metabolite

Mercaptopurine (6-MP)

Azathioprine

6-Thioguanine (6-TG)

used in: acute leukemia & chronic myelogenous leukemia

mechanism: must be activated by purine salvage pathway, induce mutations by pairing with C & T, inhibit de novo purine synthesis

High incidence of therapy induced cancer associated

TPMT enzyme test must be done before therapy

Anti-Metabolite, Thiopurine

used in: acute leukemia & chronic myelogenous leukemia

mechanism: must be activated by purine salvage pathway, induce mutations by pairing with C & T, inhibit de novo purine synthesis

High incidence of therapy induced cancer associated

TPMT enzyme test must be done before therapy

Anti-metabolite

Mechanism: blocks thymidylate synthase

works as a pyrimidine analog

Converted to FdUMP, FdUTP, or FUTP

fluorodeoxyuridine monophosphate

inhibits thymidylate synthase by blocking access of dUMP

causes dNTP imbalance and high dUTP levels, leading to DNA damage

fluorodeoxyuridine triphosphate

incorporated into DNA

induces nucleotide  excision repair, which is futile in the presence of high concentration of FdUTP/dTTP.  this leads to DNA strand breaks and cell death

incorporates into RNA

inhibits many processes like:

- processing of mRNA into mature RNA

-modification of tRNA

profound effects on cell metabolism and viability

Vinca Alkaloid

isolated from vinca rosa shrub

mechanism: targets microtubules. bind tubulin and prevent mitotic spindle formation = "metaphase arrest"

Vinblastine

mechanism: targets microtubules. bind tubuulin and prevent mitotic spindle formation = "metaphase arrest"

paclitaxel/Taxol

isolated from yew tree bark

used for: metastatic cancer of breast and ovary

mechanism:  induces polymerization/stabilization of microtubules

Taxol

Paclitaxel

Taxoids

isolated from yew tree bark

used for: metastatic cancer of breast and ovary

mechanism:  induces polymerization/stabilization of microtubules

Actinomycin D

Doxurubicin (Adriamycin)

Mitomycin

Bleomycin

Streptomyces-derived Antibiotic

mechanism:  intercalates in DNA and inhibits transcription and DNA synthesis

 (adriamycin)

Streptomyces-derived Antibiotic

mechanism: intercalates in DNA

Streptomyces-derived Antibiotic

mechanism: after intracellular synthesis, reacts with DNA and inhibits synthesis

Streptomyces-derived Antibiotic

mechanism:  chelates metal ions --> produces superoxide and hydroxide-free radicals which leads to DNA cleavage, lipid (and other) peroxidation

Topotecan / Irinotecan

isolated from camptoteca acuminata (happy tree)

mechanism:  inhibits topoisomerase I which leads to single-strand breaks in DNA 

inhibits replication and transcription

Camptothecins

isolated from camptoteca acuminata (happy tree)

mechanism:  inhibits topoisomerase I which leads to single-strand breaks in DNA 

inhibits replication and transcription

etopside / teniposide

isolated form mayapple plant

mechanism: inhibits topoisomerase II, which leads to double strand breaks in DNA

causes erroer during DNA replication and eventual apoptosis

etopside

teniposide

lance armstrong used successfully

mechanism:  intra-interstrand crosslinks in DNA

used for:  acute promyelocytic leukemia (APL)

mechanism: it works

used in combination with  ATRA (all trans retinoic acid)

conjugated to PEG and derived from bacteria

mechanism:  suppress leukemia by lowering ammonia levels

Asn --> Asp + NH₃

--Asn(asparagine) levels are depleted

( ALL leukemic cells are unable to synthesize the non-essential amino acid asparagine, whereas normal cells are able to make their own asparagine; thus leukemic cells require high amount of asparagine. These leukemic cells depend on circulating asparagine. Asparaginase, however, catalyzes the conversion of L-asparagine to aspartic acid and ammonia. This deprives the leukemic cell of circulating asparagine.)

Androgens

Anti-Androgens

Estrogen

Anti-Estrogens

Anti-Androgens and Anti-Estrogens used more than androgens and estrogens

Sex Hormone

used for: metastatic breast cancer

(not used much because may be bad)

Sex Hormone

Mechanism:  Give a very high dose = toxicity

used for:  postmenopausal breast cancer; prostate cancer

not used often beause may be bad

Aromatase inhibitor

used for: advanced breast cancer

mechanism:  prevents the conversion of testosterone to estradiol

(Aromatase is the enzyme that does the conversion)

Selective Estrogen receptor downregulators

used for:  tamoxifen resistant patients

mechanism: destruction of estrogen receptors

FULVESTRANT

(a selective estrogen receptor downregulator)

Tretinoin

Alitretinoin

Bexarotene

used for: Ph+ chronic myeloid lymphoma;

Ph+ Acute Lymphocytic Leukemia; GI stromal tumors

ASSOCIATION: Philadelphia Chromosome

mechanism:  tyrosine kinase inhibitor.

targets:

Abl (intracellularly); cKit and PDGFR (surface receptors)

what is the difference between

-mab and -nib?

-mab = monoclonal antibody

-nib = kinase inhibitor

Herceptin

used for: breast cancers with HER2 amplification

mechanism: anti-HER2 antibody

dose: IV every week during chemo and once every 3 weeks after chemo/surgery

cons: cardiac dysfunction (must be checked routinely)

(Trastuzumab)

used for: breast cancers with HER2 amplification

mechanism: anti-HER2 antibody

dose: IV every week during chemo and once every 3 weeks after chemo/surgery

cons: cardiac dysfunction (must be checked routinely)

Trastuzumab (Herceptin)

and

Lapatinib

used for: breast cancers with HER2 amplification

mechanism:  HER2/Neu and EGFR kinase inhibitor

dose: Pill taken daily

cons: nausea/vomiting/heartburn/fatigue

used for:  advanced non-small-cell lung cancer (NSCLC)

mechanism:  EGFR kinase inhibitor

PROs: + 3 months of life

CONs: rash, diarrhea, fatigue

Gefitinib (Iressa)

used for: advanced NSCLC

mechanism: EGFR kinase inhibitor

cons: acne, diarrhea, nausea, vomiting

Erlotinib (Tarceva)

and

Gefitinib (Iressa)

and 

Bevacizumab (Avastin)

used for: squamous cell carcinoma and colon cancer 

mechanism: prevents EGF binding

monoclonal antibody

***ONLY USED IN PATIENTS THAT DON'T HAVE A KRAS MUTATION***

(this is tested for before therapy can begin)

Bevacizumab (Avastin)

Sunitinib (Sutent)

Sorafenib (Nexavar)

Angiogenesis Inhibitor

used for:  NSCLC; metastatic colorectal cancer; age-related macular degeneration

mechanism: VEGF antibody

(prevents VEGF from binding to its receptor)

CONs: risk of bleeding, bowel perforation

*** was approved for metastatic breast cancer, but this was revoked in 2010***

used for: Advanced Renal cell Carcinoma (RCC); unresectable hepatocellular carcinoma

mechanism: inhibitor of VEGFR2, VEGFR3, PDGFR, cKit, Raf-1, B-Raf

used for: late stage melanoma

mechanism:inhibits v600e b-raf, not the wild-type b-raf

(60% of melanomas have the v600e b-raf mutation)

***this is a brand new drug***

used for: multiple myeloma

mechanism:  inhibits active-site for 26S proteasome

Azacitidine (Vidaza)

and 

5-Aza-2-deoxycytidine (Decitabine)

DNA Demethylating Agent

used for: myelodysplastic syndrome (pre-leukemia)

mechanism: DNA incorporation (direct and irreversible)

inhibition of DNA methyltransferase

incorporates into RNA

"reactivates" tumor suppressor genes

5-Aza-2-deoxycytidine (Decitabine)

DNA Demethylating Agent

used for: myelodysplastic syndrom (pre-leukemia)

mechanism: DNA incorporation (direct and irreversible)

inhibition of DNA methyltransferase

"reactivates" tumor suppressor genes

Histone deacetylase inhibitor

used for: cutaneous t-cell lymphoma

Vorinostat/SAHA (Zolinza)

and

Romidepsin (Istodax)

used for: colon cancer, melanoma, head, neck cancers

mechanism:  non-specific immunostimulatory properties

CONs: inflammatory destruction of RBC, leukocyte suppression

***not in US market, also, seen as a cocaine cutting agent***

Cutaneous T-Cell Lymphoma Drugs

(4)

Retinoid Bexatene (RXR)

Denileukin difitox/Onkak

-immunotoxin

-IL-2 conjugated Diptheria toxin

Vorinostat/SAHA (Zolinza)

-histone deacetylase inhibitor

Romidepsin (Istodax)

-histone deactetylase inhibitor

Off label:  Methotrexate (retards DNA, stops proteins)

Cyclophosphamide (crosslinks guanines) = lowered immunoresponse

used for:  metastatic castration-resistant prostate cancer

mechanism:  autologous cellular immunotherapy "cancer vaccine"

1)leukocytes extracted (esp. APC)

2)sent to company, fused with PAP and GM-CSF

-APC's mature

3)reintroduced into the patient

PROs: 4-month gain

used for: late-state melanoma (in clinical trials for prostrate and lung)

mechanism: human monoclonal antibody

blocks CTLA-4 

-CTLA-4 makes sure t-cell isn't always active

CONs:  potentially fatal immunological adverse effects, GI effects, fever

used for: cutaneous T-cell Lymphoma

mechanism: Immunotoxin

IL-2 conjugated to diptheria toxin

block of protein synthesis

Brentuximab vedotin (Adcetris)

used for: hodgkins lymphoma; systematic anaplastic large-cell lymphoma

mechanism:  antibody conjugated to toxin

targets CD30; stable in blood, cleaved in cell

blocks polymerization of tubulin which leads to halting of cell division