Body Surface Area.

The larger the height and weight, the higher the BSA.  this gives a better correlation between therapeutic and toxic doses.  It also correlates well with cardiac output and affects the hepatic and renal elimination of the drug.

1.  should be active alone against the tumor of interest

2.  should act by different mechanisms of action

3.  should have different dose limiting toxicities

4.  should have different mechanisms of resistance

5.  should include cell cycle specific and non-specific agents

Leucovorin:

What is it and what does it do?

Methotrexate:

1.  Class

2.  Method of action

3.  adverse effects

1.  Antimetabolite (folic acid analogue)

2.  Folic acid blocker which is needed for DNA synthesis.

3.  stomatitis

1.  Nitrogen mustards (mechlorethamine, cyclophosphamide, ifosfamide)

2.  Ethylenimines/Methylamines

3.  Nitrosoureas

4.  Miscellaneous (cisplatin, carboplatin, temozolomide)

Mechlorethamine:

1.  Class

2.  Method of action

3.  Adverse effects

1.  alkylating agent

2.  Bind to DNA and stop DNA synthesis

This was the first alkylating agent

Cyclophosphamide

1.  Class

2.  Method of Action

3.  adverse effects

1.  Alkylating agent (nitrogen mustard)

2.  Bind to DNA to stop DNA synthesis

3. hemorrhagic cystitis

Ifosfamide:

1.  Class

2.  Method of action

3.  adverse effects

1.  alkylating agent (nitrogen mustard)

2.  Bind to DNa to stop DNA synthesis

3.  hemorrhagic cystitis

Cisplatin

1.  Class

2.  Method of action

3.  adverse effects

4.  uses

1.  miscellaneous alkylating agent

2.  Bind to DNA to stop DNA synthesis

3. renal toxicity

4.

Carboplatin:

1.  Class

2.  Method of action

1.  Miscellaneous alkylating agent

2.  Bind to DNA to stop DNA synthesis

Temozolomide:

1.  Class

2.  Method of Action

3.  Adverse effects

4.  Uses

1.  Miscellaneous Alkylating Agent

2.  Bind to DNA to stop DNA synthesis

They are intercalators so they insert themselves in the DNA to stop DNA synthesis.  This is not binding like with the alkylators though. 

Examples include doxorubicin and epirubicin.

Doxorubicin

1.  Class

2.  Method of action

3.  adverse effects

1.  Anthracycline (antibiotic)

2.  Intercalation

3.  cardiovascular toxicity

Epirubicin

1.  Class

2.  Method of action

3.  Adverse Effects

1.  Anthracycline (antibiotic)

2.  intercalation

3.  cardiovascular toxicity

Bleomycin

1.  Class

2.  Method of action

3.  Adverse Effects

4.  Uses

1.  Miscellaneous antibiotic

2.  creates reactive oxygen species to cause DNA strand breaks (random breaks)

3. pulmonary toxicity

4.

They block the biosynthesis or use of normal cellular metabolites.  This results in less DNA synthesis.  This can be from removal of critical proteins in DNA replication or false substrates for DNA synthetic enzymes. 

Antimetabolites work better in slow growing tumors than many of the alkylating agents.  Why?  Because they act upstream of the DNA target.

Fluorouracil (5-FU):

1.  Class

2.  Method of action

3.  adverse effects

4.  Uses

1.  Antimetabolite (pyrimidine)

2.  this stop thyine synthesis by being a false substrate.

3.  stomatitis

4.

Gemcitabine

1.  Class

2.  Method of Action

3.  Adverse effects

4.  Uses

1.  Antimetabolite (pyrimidine)

2.  This stops DNA synthesis by being a pyrimidine analogue

3.

4.

The bine stops the pyrimidine.

Capecitabine

1.  Class

2.  Method of Action

1.  Antimetabolite (pyrimidine)

2.  Stops pyrimidine synthesis by being an analogue

Remember, the bine stops the pyrimidine.

6-mercaptopurine

1.  Class

2.  Method of action

1.  Antimetabolite (purine analog)

2.  Stops DNA synthesis by being a purine analogue

What are the different classes of plant alkaloids?

(4)

1.  Vincas

2.  Camptothecins

3.  Epipodophyllotoxins

4.  Taxenes

Vincristine

1.  Class

2.  Method of Action

3.  Adverse Effects

4.  Uses

1.  Plant Alkaloid (Vincas)

2.  prevent the formation of the mitotic spindle

3. neurotoxicity (neuropathy) - numbness, trouble walking, loss of reflexes

4.

Vinblastine

1.  Class

2.  Method of Action

3.  Adverse Effects

4.  Uses

1.  Plant alkaloids (vincas)

2.  prevent the formation of the mitotic spindle

3. 

4.

Irinotecan

1.  Class

2.  Method of action

3.  adverse effects

1.  Plant Alkaloid (camptothecins)

2.  inhibit topoisomerase I which causes DNA strand breaks

3.  diarrhea

Topotecan

1.  Class

2.  Method of action

3.  adverse effects

1.  Plant alkaloid (camptothecin)

2.  Inhibits topoisomerase I which causes DNA strand breaks.

3.  diarrhea

etoposide

1.  Class

2.  Method of action

1.  Plant Alkaloid (epipodophyllotoxin)

2.  Inhibits topoisomerase II which causes DNA strand breaks

teniposide

1.  Class

2.  Method of action

1.  plant alkaloid (epipodophyllotoxin)

2.  Inhibits topoisomerase II which causes DNA strand breaks

Paclitaxel

1.  Class

2.  Method of action

1.  Plant alkaloid (taxene)

2.  Stabilize microtubules which blocks cell division

docetaxel

1. Class

2.  Method of action

1. plant alkaloid (taxene)

2.  stabilize microtubules which blocks cell division

This is the better one in the class because it doesn't have to be given by IV and it doesn't take as long.

Asparaginase

1.  Class

2.  Method of action

1.  miscellaneous ?

2.  removes asparagine from the tumor cell which is vital for its growth

pegasparagine

1.  class

2.  method of action

1.  miscellaneous ?

2.  removes asparagine from tumor cell which is vital for its growth

levamisole

1.  class

2.  method of action

1.  miscellaneous?

2.  this is an antihelmitic drug that non-specifically stimulate the immune system

This is used as an adjunct agent in colon cancer

Bacillus Calmette-Guerin (BCG)

1.  Class

2.  Method of action

3.  Adverse Effects

4.  Uses

1.  Miscellaneous?

2.  Vaccine against bovine bacteria that non-specifically enhances the immune system to fight the cancer cells

3.

4.  Used for bladder cancers

Myelosuppression

It also causes neutropenia, erythropenia, thrombocytopenia, anemia

This is why you do chemo in a cycle.  Onset of suppression is 7 days, it is worst at 10-14 days, and you are normal by 28 days.

You can have extravasation necrosis.  This causes localized tissue damage. 

Vincas:  administer heat and hyaluronidase

Use sodium thiosulfate for mechlorethamine

Hyaluronidase

What is it?

Ondansetron

1.  Class

2.  Method of Action

1.  5HT3 antagonist

2.  Stops the vomiting reflex in the chemo patients.

granisetron

1.  class

2.  Method of Action

1.  5HT3 antagonist

2.  stops the vomiting reflex in the chemo patients

1.  topotecan

2.  irinotecan

Bleomycin

This is inactivated by an enzyme that is not present in the lung so it causes problems.  this can also be a problem with mitomycin and nitrogen mustards.

Cisplatin - direct renal cell death

amifostine - sulfhydryl containing drug that detoxifies free radicals that can lead to renal cells death, so this is a treatment.

Amifostine

1.  class

2.  Method of action

1.  sulfhydryl containing drug

2.  Used to treat renal toxicity that is associated with cisplatin by detoxifying the free radicals that lead to renal cell death.

Anthracyclines.  These are the intercalators.  They are doxorubicin and epirubicin.

The damage is proportional to total cumulative dose.  This is caused by an increase in reactive oxygen species in the myocardium.  To treat it you need to chelate the iron to lower the reactive oxygen species (dexrazoxane).

Acrolein

1.  Class

2.  Method of Action

1.  This is a breakdown product of the fosfamides (nitrogen gases)

2.  Causes hemorrhagic cystitis

MESNA is the treatment that inactivates it.

They are used to stimulate the growth of bone marrow and its cells to help the myelosuppression that occurs with chemo treatment.

they are usually human proteins, mostly recombinant products, unstable, cannot be administered orally. 

They are expensive.  Remember that.

Aldesleukin (IL-2)

1.  Class

2.  Method of action

3.  Uses

4.  Adverse effects

1.  Interleukin

2.  This is a T cell growth factor

3.  Renal cell carcinoma

4.  capillary leak.  this is very severe and common if you have a high dose of IL-2.  This usually occurs in the lung due to activated T cells that damage the endothelium.

Can also cause myelosuppression of other types of bone marrow derived cells.

Interferon alpha 2A (intron A)

1.  Class

2.  Method of Action

3.  Adverse Effects

4.  Method of Admin

5.  Uses

1.  Interferon

2.  Increases phagocytic activity of macs and increases cytoxicity of lymphocytes

3.  flu-like syndrome, myelosuppression

4.  IV (short half-life)

Interferon Gamma

1.  Class

2.  Method of action

3.  adverse effects

1.  interferon

2.  activates phagocytes to generate toxic oxygen metabolites within themselves that can kill target cells

3.  flu-like syndrome

Erythropoietin

1.  Class

2.  Method of action

3.  Use

4.  adverse effects

1.  ?

2.  stimulates stem cells to take the route of committed erythrocyte precursor (RBCs).  It takes 2-6 weeks to see the effects

3.  Anemia associated with chemo.  You should always measure the plasma erythropoietin levels to make sure that is the cause of the anemia. 

4.  headache, iron deficiency in the blood

DO NOT USE IN ERYTHROID-BASED TUMORS.

Granulocyte colony stimulating factor (G-CSF)

1.  Method of Action

2.  Uses

3.  Adverse Effects

1.  increases neutrophil precursors = increased number of neutrophils

2.  give with chemotherapy that is known to cause neutropenia

3.  fever, bone pain, flu-like symptoms

DO NOT USE WITH LEUKEMIAS.

Granulocyte macrophage colony stimulating factor (GM-CSF)

1.  Method of Action

2.  Adverse effects

1.  increase monocyte and granulocyte precursors to increase monocyte/mac killing of tumor cells.  at higher doses, it stimulated RBC and platelet precursors. 

2.  bone and muscle pain, fever, rash

DO NOT USE WITH LEUKEMIAS.

Bexarotene

1.  Class

2.  Method of Action

3.  adverse effects

1.  Vitamin A derivative

2.  Bind to RXR receptor (promicuous one) to induce tumor cell differentiation to become mature, non-malignant cells. 

3.  sensitivity to sunlight.

Denileukin Diftitox

1.  Method of Action

2.  Use

1.  This is IL-2 attached to diphtheria toxin.  IL-2 targets drug to T cells and diphtheria toxin kills the T cells. 

2.  T cell lymphoma

Trastuzumab

1.  Method of Action

2.  Half life

3.  Adverse rxns

4.  Interactions with other drugs

1.  This is an antibody that blocks EGF from binding to the Her2/neu receptor

2.  18-27 days which is very good

3.  cardiomyopathy

4.  trastuzumab and anthracycines (rubicins) shouldn't be used together because of toxicity

Iapatinib

1.  Method of Action

2.  Metabolism

1.  This is a kinase inhibitor that blocks her2/neu kinase activity to stop growth in breast cancers

2.  Metabolized by CYP3A4 in the liver

Gefitinib

1.  Class

2.  Method of action

3.  Uses

4.  adverse rxns

5.  resistance

1.  EGFR-1 tyrosine kinase inhibitor

2.  stop tyrosine kinase

3.  NSCLC, GI stoma

4.  GI, diarrhea

5.  EGFR and IGF-I R mutations can cause resistance, so can a k-Ras mutation downstream of EGFR

Erlotinib

1.  Class

2.  Method of Action

3.  Uses

4.  Resistance?

1.  EGFR-1 tyrosine kinase inhibitor

2.  stop tyrosine kinase

3.  NSCLC, pancreatic cancer (along with gemcitabine - pyrimidine analogue)

4.  EGFR and IGF-Ir mutations and K-Ras mutations can cause problems

Cetuximab

1.  Method of action

2.  Method of admin

3.  Use

4.  Adverse rxns

5.  Resistance?

1.  anti EGFR I monoclonal antibody

2.  IV

3.  Colon cancer, sqamous cell head and neck cancer

4.  infusion sensitivity in some cases (pretreat with histamine blockers to stop hypersensitivity)

5.  K-Ras mutation can cause resistance so only use it if they have a normal Ras

Imatinib

1.  Method of action

2.  Adverse Rxns

3.  uses

1.  inhibits the BCR-abl kinase

2.  GI problems are common, Edema, hepatotoxicity

3.  leukemias

bevacizumab

1.  method of action

2.  half life

3.  use

4.  adverse reactions

1.  monoclonal antibody against VEGF

2.  20 days this is really good

3.  colon, NSCLC, breast, renal cell

4.  GI problems and epistaxis

sorafenib

1.  method of action

2.  uses

3.  adverse rxns

1.  inhibitor of VEGFR-2 and PDGFR beta kinase and also c-Kit and VEGFR-3 kinase

2.  liver and renal cancer

3.  fatigue

sunitinib

1.  method of action

2.  uses

3.  adverse rxns

1.  inhibits VEGFR-2 and PDGFRbeta kinase

2.  renal and gefitinib resistant GIS tumors

3.  fatigue