Anti-Cancer Drugs

1. Cyclophosphamide
2. Mechlorethamine
3. Cisplatin
4. Lomustine

What are the 4 alkylating agents?

Cyclophosphamide

*since it's a prodrug and not a vesicant

Which alkylating agent has an oral (w/ food) option?

1. Cyclophosphamide (a prodrug)

2. Mechlorethamine

3. Cisplatin

Alkylates/crosslinks DNA --> DNA damage in any phase of the cell cycle (cell cycle non-specific) --> apoptosis

Lomustine

Crosses the BBB and can be used to treat CNS cancers...

Which alkylating agent?

1. Mechlorethamine

2. Cisplatin

*they're both vesicants

Which alkylating agents are IV only?

Bone marrow suppression

What is the dose limiting toxicity of cyclophosphamide and mechlorethamine (2 alkylating agents)?

Cyclophosphamide

*thus it's not considered a vesicant

Which alkylating agent is a prodrug?

Cyclophosphamide

AE:

1. Marrow suppression

2. Acute hemorrhagic cystitis

3. Pancytopenia

Which alkylating agent?

Pregnancy (Class D) --> avoid in lactating women

Major CI of alkylating agents (Cyclophosphamide, Mechlorethamine, Cisplatin)

1. Mechlorethamine
2. Cisplatin

Which 2 alkylating agents are vesicants (causes local injury due to extravasation) and must be given IV?

Mechlorethamine

AE:

1. Marrow suppression

2. Vesicant

*similar to mustard gas

Which alkylating agent?

Cisplatin

AE:

1. Nephrotoxicity

2. Vesicant

3. Ototoxicity & neurotoxicity

4. Severe nausea/vomiting

Which alkylating agent?

Nephrotoxicity

*administer Amifostine to protect from renal toxicity

What is the dose limiting toxicity of Cisplatin (an alkylating agent)?

Lomustine

*can cross BBB

Indication:

CNS cancer

Which alkylating agent?

1. Mechlorethamine (alkylating agent)

2. Cisplatin (alkylating agent)

3. Methotrexate (anti-metabolite)

4. Doxorubicin (anti tumor abx/topoisomerase 2 inhibitor)

5. Vincristine (mitotic inhibitor)

What are the 5 vesicants that we need to know?

1. Alkylating agents

> cyclophosphamide

> mechlorethamine

> cisplatin

> lomustine

2. Anti tumor abx

> doxorubicin

> bleomycin

Which drug classes can affect any stage of the cell cycle?

1. 5-FU
2. Methotrexate
3. Leucovorin

What are the 3 anti-metabolite drugs?

5-FU

Block metabolic pathways required for cell growth (S phase of the cell cycle) --> blocks DNA synthesis (does not damage DNA) -->

*prodrug --> FdUMP

*thymidylate synthase inhibitor

Methotrexate

Block metabolic pathways required for cell growth (S phase of the cell cycle) --> blocks DNA synthesis (does not damage DNA)

*DHFR inhibitor

5-FU

Which anti-metabolite drug is a prodrug?

5-FU

Which anti-metabolite is indicated for rapidly growing tumors?

Methotrexate

*a vesicant

Indication:

1. rapidly growing tumors

2. organ transplants

3. rheumatology (arthritis, psoriasis, etc)

*IV only

Which anti-metabolite drug?

Marrow suppression

What is the dose limiting toxicity of Methotrexate?

Methotrexate

Which anti-metabolite is a vesicant?

Methotrexate

AE:

1. Vesicant

2. Marrow suppression

3. Pulmonary infiltration and fibrosis

4. Oral/GI ulceration (death from intestinal perforation and hemorrhagic enteritis)

Which anti-metabolite?

Leucovorin

*usually combined w/ MTX to make MTX selectively toxic to cancer cells

Allows synthesis of FH4 (N5, N10 methylene FH4) --> rescues normal cells

Leucovorin

Indication:

1. combo rescue therapy w/ higher doses of MTX (for cancer cells that are resistant to MTX alone)

S phase

Anti-metabolites (5-FU, MTX, Leucovorin) affect the ________ phase of the cell cycle

Anti-metabolites

> 5-FU

> MTX

> Leucovorin

Topoisomerase 1 inhibitors

> Topotecan

> Irinotecan

Which drug classes affect the S phase of the cell cycle only?

1. Doxorubicin (anthracycline/topoisomerase 2 inhibitor)

2. Bleomycin (non-anthracycline)

What are the 2 anti tumor antibiotics we need to know?

Doxorubicin (also a topoisomerase 2 inhibitor)

Which anti tumor antibiotic is an anthracycline?

Bleomycin

Which anti tumor antibiotic is a non-anthracycline?

Doxorubicin

Which anti tumor antibiotic is a vesicant?

Adriamycin = toxic

Doxil = less toxic

What are the 2 IV formulations of Doxorubicin? Which one is less toxic?

Adriamycin

Which IV formulation of Doxorubicin is more cardiotoxic?

Doxil

Which IV formulation of Doxorubicin is less cardiotoxic?

Doxorubicin

Anthracycline --> intercalates into DNA --> blocks DNA synthesis and damages DNA by catalyzing formation of free radicals

*also a potent topoisomerase 2 inhibitor

Cardiotoxicity

What is the dose limiting toxicity of Doxorubicin?

Doxorubicin

AE:

1. Cardiotoxicity

2. Marrow suppression

3. Vesicant

Which anti tumor antibiotic?

Dexrazoxane

Which drug is Doxorubicin usually combined w/ in order to reduce the amount of cardiotoxicity it causes?

Doxorubicin

Which anti tumor antibiotic is a substrate for P-gp (MDR1)?

Bleomycin

Which anti tumor antibiotic has minimal myelosuppression as an AE and is therefore very useful in combo therapy?

Bleomycin

Non-anthracycline --> binds DNA --> causes cleavage

Bleomycin

AE:

1. Pneumonitis... can progress to pulmonary fibrosis (dry coughs)

Which anti tumor antibiotic?

Any stage

Which stage of the cell cycle can anti tumor antibiotics (Doxorubicin and Bleomycin) affect?

1. Leuprolide (GnRH agonist)

2. Flutamide (Androgen receptor antagonist)

3. Degarelix (GnRH receptor antagonist)

4. Abiraterone acetate (CYP17A1 inhibitor)

What are the 4 hormonal therapies we need to know for anti-cancer treatment?

Leuprolide

GnRH agonist --> initial increase in testosterone synthesis --> GnRH receptors desensitize --> decreased testosterone

Leuprolide (GnRH agonist)

Indication:

1. Almost always combined w/ a testosterone antagonist

Which hormonal therapy?

Leuprolide (GnRH agonist)

AE:

1. Decreased androgens

2. Initial flare of cancer symptoms

3. Hot flashes

4. Loss of libido and muscle mass

5. Osteoporosis

Which hormonal therapy?

Flutamide (androgen receptor competitive antagonist)

Indication:

1. Prostate cancer (combo w/ GnRH agonist Leuprolide)

Which hormonal therapy?

Flutamide

Androgen receptor competitive antagonist

Flutamide (androgen receptor competitive antagonist)

Which hormonal therapy can cause gynecomastia as an AE?

Degarelix (GnRH receptor antagonist)

Indication:

1. Prostate cancer (extended release formulation)

Which hormonal therapy?

Degarelix

Blocks GnRH receptors in the pituitary --> decreased LH --> decreased testosterone

Abiraterone acetate (CYP17A1 inhibitor)

*very expensive and doesn't work well

Indication:

1. Metastatic Castration-Resistant Prostate Cancer (CRPC)

> combo w/ prednisone in patients who have received prior chemotherapy containing docetaxel

Which hormonal therapy?

Abiraterone acetate

CYP17A1 inhibitor --> decreased testosterone synthesis

1. Topotecan (topoisomerase 1 inhibitor, S phase only)

2. Irinotecan (topoisomerase 1 inhibitor, S phase only)

3. Doxorubicin (topoisomerase 2 inhibitor, any phase)

What are the 3 topoisomerase inhibitors?

1. Topotecan
2. Irinotecan

Prodrug --> SN-38 (topoisomerase 1 inhibitor) --> prevents unwinding of DNA during replication (S phase specific)

Topotecan

Which topoisomerase inhibitor causes marrow suppression as an AE?

UGT1A1

Patients w/ what polymorphism will deactivate SN-38, making Irinotecan (a topoisomerase 1 inhibitor prodrug) useless?

Dexrazoxane

Indication:

1. Breast cancer (combo w/ Doxorubicin)

2. Local injury from extravasation due to vesicants

Dexrazoxane

Converted to an iron chelator (ICRF-198) --> prevents iron from chelating w/ Doxorubicin --> decreases heart failure, but intensifies myelosuppression

1. Stop the IV immediately
2. Administer Dexrazoxane (an iron chelator)

What should you do if a patient is experiencing local injury from extravasation due to inappropriate vesicant use?

Filgrastim

G-CSF --> stimulates granulocyte production from marrow

Filgrastim (G-CSF)

Indication:

Patients taking myelosuppressive anti-neoplastic agents

Ondansetron (Zofran)

Indication:

Chemotherapy-induced nausea/vomiting

Ondansetron (Zofran)

5-HT3 receptor antagonist --> blocks serotonin receptors in brain and GI tract --> prevents nausea & vomiting

Amifostine

Indication:

1. Renal/nephrotoxicity associated w/ repeated Cisplatin use in patients w/ advanced ovarian cancer

2. Xerostomia caused by radiation therapy in head and neck cancers

Amifostine

Prodrug --> converted to WR-1065 by alkaline phosphatase --> acts as a scavenger of free radicals generated during chemotherapy or radiation therapy

1. Paclitaxel (taxane)

2. Vincristine (vinca alkaloid)

What are the 2 mitotic inhibitors we need to know?

Paclitaxel

Indication:

Breast cancer

Which mitotic inhibitor?

Paclitaxel

Taxane (from the pacific yew) --> acts during M phase to prevent cell division (increases polymerization of microtubules and prevents depolymerization)

Paclitaxel

AE:

1. Marrow suppression

2. Neurotoxicity

3. Hypotension

4. Bradycardia

Which mitotic inhibitor?

Vincristine

Which mitotic inhibitor is a vesicant?

Vincristine

Which mitotic inhibitor is bone marrow sparing and is thus ideal for combo therapy?

Vincristine

Alkaloid --> acts during M phase to prevent cell division (prevents assembly of microtubules)

Neurotoxicity

What is the dose limiting toxicity of Vincristine?

Vincristine

AE:

1. Neurotoxicity (peripheral neuropathy... decreased reflexes and sensory loss)

2. Vesicant

3. Liver toxicity

Which mitotic inhibitor?

Mitotic inhibitors
> paclitaxel
> vincristine

Which class of drugs only affects the M phase of the cell cycle?

M phase

Paclitaxel & Vincristine affect the ________ phase of the cell cycle

1. Trastuzumab
2. Pertuzumab
3. Trastuzumab emtansine (T-DM1)
4. Cetuximab

What are the 4 growth factor receptor MAbs?

Trastuzumab

Indication:

HER2+ breast cancer

Which growth factor receptor MAb?

Trastuzumab

MAb that targets HER2 (tyrosine kinase growth factor) receptor --> blocks growth signals and flags cancer cells for destruction by the immune system

*binds specifically to the extracellular domain of the HER2 protein

*inhibits PI3K/AKT & MAPK pathways

*also causes antibody-dependent cellular cytotoxicity (ADCC)

*triggers endocytosis/internalization of the HER2 receptors

Trastuzumab

Which growth factor receptor MAb can cause cardiotoxicity when combined w/ Doxorubicin?

Pertuzumab

Indication:

HER2+ breast cancer (recurrent and metastatic... used in combo w/ Trastuzumab & Cyclophosphamide)

Which growth factor receptor MAb?

Pertuzumab

MAb that binds to different site on HER2 receptor (compared to Trastuzumab) --> decreased activation of Ras/MAPK and PI3K pathways --> works synergistically w/ Trastuzumab to provide a more comprehensive blockade of HER2 signaling pathways

Pertuzumab

Which growth factor receptor MAb can cause diarrhea and alopecia as AE?

Trastuzumab emtansine (T-DM1)

Indication:

HER2+ breast cancer (patients who previously received Trastuzumab and a taxane, separately or in combo... or those who developed disease recurrence during or within 6 months of completing adjuvant therapy)

Which growth factor receptor MAb?

Trastuzumab emtansine (T-DM1)

Antibody-drug conjugate combo w/ a microtubule polymerization inhibitor bound via a stable thioether linker

Cetuximab

Indication:

Advanced colorectal cancer (can be combined w/ Irinotecan)

Which growth factor receptor MAb?

Cetuximab

MAb which targets EGF receptor --> blocks growth of cancer cells

Bevacizumab

MAb that blocks VEGF --> cuts off blood vessel growth

Cetuximab = targets EGF receptor

Bevacizumab = targets VEGF

Cetuximab vs Bevacizumab targets

1. GI perforation
2. Disruption of wound healing
3. Pulmonary hemorrhage

Major AE of Bevacizumab (VEGF inhibitor)

1. Imatinib
2. Erlotinib
3. Osimertinib
4. Larotrectinib

What are the 4 protein tyrosine kinase inhibitors?

Imatinib (Gleevec)

Indication:

Chronic Myelogenous Leukemia (CML)

Which protein tyrosine kinase inhibitor?

Imatinib (Gleevec)

Inhibits BCR-ABL tyrosine kinase

Neutropenia & thrombocytopenia

Major AE of Imatinib (Gleevec)

Erlotinib

Reversible inhibitor of the EGFR tyrosine kinase --> competitively inhibits ATP binding at the active site of the kinase

Erlotinib = reversible inhibitor of EGFR

Osimertinib = irreversible inhibitor of T790M-mutant EGFR

Erlotinib vs Osimertinib MOAs