8/26- Common Cancer Drugs 2: Targeted Therapy Flashcards Preview

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Flashcards in 8/26- Common Cancer Drugs 2: Targeted Therapy Deck (31):

How can corticosteroids be used for targeted cancer therapy (what are hormone interaction characteristics of tumors)?

Tumors that are steroid hormone-sensitive may be either:

1. Hormone responsive -> tumor regresses following hormone treatment

2. Hormone dependent -> removal causes tumor regression

3. Hormone dependent -> antagonism can block & cause tumor regression


What is a corticosteroids that may be used?



What is Prednisone?

- Characteristics

- Uses

Potent, synthetic, anti-inflammatory corticosteroid

- Used to induce remission in patients with ALL

- Used to treat both Hodgkin and non-Hodgkin lymphomas

Prednisone has the ability to destroy (or severely limit) lymphocytes; leukemias that result from uncontrolled growth of lymphocytes respond to treatment.


What is the mechanism of Prednisone?



Mechanism: binds to HREs and alters transcription

Resistance: receptor is absent or mutated to a low-affinity form

Pharmacokinetics: readily absorbed orally; binds to plasmin albumin and transcortin


What are the ASEs of Prednisone?

- Immunosuppression

- GI ulcers and pancreatitis

- Cushing's Syndrome


What are some sex hormone agonists and antagonists that may be used for targeted cancer treatment?

- Estrogens

- Tamoxifen


How is estrogen used for cancer treatment?



- Estrogens such as ethinyl estradiol or diethylstilbestrol were used in the treatment of prostate cancer

- Estrogens inhibit the growth of prostatic tissue by blocking the production of LH in the pituitary, thereby reducing androgen synthesis in the testis.

Not as big a role anymore

- They have been largely replaced by the GnRH analogs because of fewer adverse effects


What is Tamoxifen?

- Mechanism

- Resistance

- Uses

An estrogen antagonist

- Classified as a SERM (selective estrogen-receptor modulator)

- Currently approved for 5 yrs of prophylactic use for women at high risk of BC

Mechanism: interferes with the action of natural estrogens in ER+ breast cancers

- Binds to the estrogen receptor, but the complex is not transcriptionally active


- Fewer E receptors

- Decreased affinity

- Dysfunction


- First line therapy to treat estrogen receptor positive breast cancer!!

- Weak estrogenic activity -> endometrial CA

- 40-50% positive response in breast cancer and prophylactic therapy

- New results: stopping treatment at 5 yrs (rather than 8 yrs) --> a small but significant benefit in DFS and a trend favoring overall survival


Details on Tamoxifen:

- Pharmacokinetics

- ASEs

- Effective on oral administration

ASEs: similar to natural estrogens

- Hot flashes, nausea, and fluid retention

- 2x increase in endometrial CA

- Thromboembolic risk


What is GnRH?

What are GnRH agonists and antagonists used for?

Normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete LH and FSH which cause stimulation of gonadotropin secretion

 - Used for types of prostate cancer hormone therapy 


How do GnRH agonists work? Antogonists?

Agonists -> chemical castration

- Cause a huge, but brief, flare in testosterone production

- Feedback of “flare levels” block further testosterone production

Antagonists -> blocks pituitary

- Pituitary loses responsiveness to GnRH


What are some GnRH agonists?

Injected once daily:

- Leuprolide

- Histerelin

Nasal spray:

- Nafarelin

Depot preparation:

- Leuprolide


What is Leuprolide?

- Mechanism

- Uses

Analog of GnRH

- Binds to GnRH receptor in the pituitary

- Cause desensitization of...

- Results in inhibition of release of FSH and LH

- Both androgen and estrogen synthesis are reduced


- Response to leuprolide in prostatic cancer is equivalent to orchiectomy

- Leuprolide has largely replaced estrogen in therapy for prostate cancer

- Some benefit seen in premenopausal women with advanced breast cancer


What are some GnRH antagonists?

- Abarelix

- Triptorelin

(Peptide antagonists of the GnRH receptor)


What is Abarelix?

- Unique

- Mechanism

- Uses

GnRH antagonist

- Does not exhibit the "flare phenomenon" of GnRH agonists


What is Triptorelin?

- Unique

- Mechanism

- Ueses

GnRH antagonist

- Reduces the production of LH and causes testosterone levels to fall, but may exhibit a ‘flare phenomenon’


What are aromatases?

Responsible for the extra-adrenal gland synthesis of estrogen from testosterone.

- Found in: iver, fat, muscle, skin, and breast tissues


What are classes of aromatase inhibitors? Agents?


- Aminoglutethimide

- Steroids

- Imidazoles


- Anastrozole 

- Ietrozole


What is the mechanism of aromatase inhibitors?

Adverse side effects?

Selective inhibition of aromatase results in less conversion of androgen to estrogen


- Thromboembolism

- Fractures

- Cataracts

- Endometrial CA


Uses of aromatase inhibitors?

- Advanced ER+ and PR+ breast cancers

 - Breast cancer prevention trials


What is Exemestane?

- Mechanism

- Absorption

- ASEs

- Contraindications

- Irreversible inhibitor of aromatase

- Steroidal

- Well absorbed orally

- Toxicities include: nausea, fatigue and hot flashes

- Metabolites excreted in urine, hence dosage must be lowered if patient is in renal failure


What is Anastrozole?

- Benefits

- ASEs

- Imidazole aromatase inhibitors

- nonsteroidal

- More potent

- More selective

- Hydrocortisone supplementation not needed

- Do not predispose to endometrial cancer

- Devoid of androgenic side effects

- Second line in US; first line in other countries


What is Imatinib (Gleevec)? Uses?

An inhibitor of a specific protein tyrosine kinases that was targeted to the platelet-derived growth factor receptor (PDGF-R).

- It was found to inhibit the constitutively active fusion product arising from the Philadelphia (Ph) chromosome of chronic myelogenous leukemia (CML) and c-kit (CD117), which is overexpressed in GI stromal tumors.

Recently approved for:

- CML refractory to interferon therapy

- GI stromal cancers


What are some ASEs of Imatinib?

- fever, sore throat, and headache with a severe blistering, peeling, and red skin rash;

- nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

- fever, chills, body aches, flu symptoms;

- black, bloody, or tarry stools;

- coughing up blood or vomit that looks like coffee grounds;

- pale skin, easy bruising or bleeding, unusual weakness;

- feeling short of breath, even with mild exertion;

- swelling, rapid weight gain;

- urinating more or less than usual, or not at all

- sudden, severe headache or pain behind the eyes.

Less severe:

- mild nausea, diarrhea, upset stomach

- muscle or joint pain

- skin rash

- headache, dizziness

- stuffy nose, cough, sore throat

- depression, sleep problems (insomnia) tired feeling.


Mechanism of angiogenesis inhibitors?

Inhibition of angiogenesis usually involves the neutralization of angiogenic factors such as VEGF (vascular endothelial growth factor) or bFGF (basic fibroblast growth factor)


What is Bevacizumab (Avastin)? Uses?

Angiogenesis inhibitor

- An IgG1 monoclonal Ab


- Colorectal cancer that has spread to other parts of the body (with other drugs)

- Some non-small cell lung cancers

- Some breast cancers that have spread to other parts of the body.

Other similar drugs have been approved for:

- Multiple myeloma

- Mantle cell lymphoma

- GI stromal tumors

- Kidney cancer


Name a proteosome inhibitor agent

Bortezomib (Velcade)


What is Bortezomib (Velcade)?

- Mechanism

- Uses

Proteosome inhibitor

- Reversible inhibitor of the 26S proteasome, (a multienzyme protease that degrades misfolded or redundant proteins) involved in signal transduction and regulation of the cell cycle

- Blockade of this pathway results in accumulation of unwanted proteins and cell death -> apoptosis

- Cancer cells, because they are more highly proliferative than normal cells, have higher rates of protein translation and degradation


- Newly diagnosed and refractory multiple myeloma

- Relapsed mantle cell lymphoma (MCL) 


ASEs of Bortezomib?

- General weakness

- Nausea

- Vomiting

- Diarrhea

- Stomach pain

- Anxiety

- Back pain

- Bone, joint, or muscle pain

- Muscle cramps

- Difficulty falling asleep or staying asleep



Traditional Chemotherapy is a form of cancer treatment that involves taking one or more drugs that interfere with the DNA (genes) of fast-growing cells. These drugs are further subdivided into specific classes such as alkylating agents, antimetabolites, anthracyclines, and topoisomerase inhibitors.

Targeted Cancer Therapies are drugs that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression while sparing normal healthy cells.



Summary Table