Cancer drugs

Name the 5 categories of DNA-reactive drugs

1. Nitrogen mustards: Mustine, Chlorambucil, Bendamustin

2. Phosphoramide mustards: Cyclophosphamide

3. N-Alkyl-N-Nitrosoureas: Carmustine; Lomustine

4. Alkylating agents: Procarbazine, Dacarbazine, Temozolomide

5. Platinum compounds: Cisplatin, Carboplatin, Oxaliplatin

Name the 3 antimetabolites?

1. Thymidylate synthase inhibitors: 5FU, Capecitabine

2. Dihydrofolate reductase (DHFR) inhibitor: Methotrexate

3. DNA replication inhibitor: Gemcitabine, Fludarabine, Cytarabine

Name the 5 Natural Product Antitumor Antibiotics

1. DNA topoisomerase II inhibitors: Doxorubicin (DNA intercalators) and Etoposide (Non intercalator)

2. DNA topoisomerase I inhibitors: Camptothecin, Topotecan, Irinotecan

3. Transcription inhibitor: Actinomycin D

4. DNA degradation: Bleomycin

5. Mitotic inhibitors: Vinca alkaloids, Paclitaxel and Docetaxel

Name the antibody therapy?

1. HER2

2. EGFR

3. VEGF

4. CD20

5. PD-1

6. CTLA-4

What is the difference between chlorambucil and mustine?

1. Oral - Aryl substituted nitrogen mustard with aromatic ring

2. Less likely to form aziridinium ion - N decreases nucleophilicity of nitrogen

3. Acts more slowly and less toxic than mustine

What class of drug is cyclophosphamide?

1. Phosphoramide mustard

2. An alkylating agent - PRODRUG

What class of drug is camustine?

N-alkyl-N-nitrosoureas - Nitrogen Mustards

What class of chemotherapy are procarbazine, dacarbazine, and temozolomide?

DNA reacting drugs - alkylating agents

form methyldiazonium ion

Imidazocarboxamides

What are key differences between dacarbazine and temozolomide?

1. Dacarbazine = imidazole carboxamide

2. Temozolomide = imidazo-tetrazine

TMZ does NOT require metabolic activation via cytochrome P450 enzymes

What is the mechanism of action of platinum compounds?

Platinum compounds react with DNA in vivo, causing monoalkylation or crosslinking of DNA which ultimately triggers apoptosis (programmed cell death)

What is a primary MOA of 5-FU? Is this drug a reversible or irreversible inhibitor?

5-FU is activated by anabolism to 5-deoxyuridyl monophosphate (Fdump), which acts as an irreversible thymidylate synthase (TS) inhibitor.

___ is an oral prodrug form of 5-FU?

Capecitabine

Metabolized to 5-FU

What are the structural features of gemcitabine?

1. 2 H atoms at 2C of deoxycytidine are replaced by fluorine atoms

2. Looks like deoxycytidine

What is the MOA of gemcitabine?

1. Diphosphate form (dFdCDP) - strong inhibitor of ribonucleotide reductase - inhibits synthesis of dNDP from NDP

2. Triphosphate form: replaces dCTP during DNA replication - arresting DNA synthesis followed by tumor growth arrest and apoptosis

Fludarabine is a ______ analogue, whereas cytarabine is a ____ analogue. Both are DNA _____ inhibitors

1. Purine analogue, pyrimidine analog

2. DNA synthesis inhibitors - interferes with ribonucleotide reductase + DNA polymerase

Methotrexate’s primary molecular target is ______, which is an enzyme essential for DNA synthesis and cell replication

1. Inhibits the enzyme dihydrofolate reductase (DHFR)

   1. Inhibits DNA synthesis in S phase

What is the MOA of bleomycin on DNA?

1. Forms a chelate with iron

2. Binds to DNA → causing generation of free radicals

3. Causes DNA strand breaks

What is the major side effect of bleomycin?

Pulmonary fibrosis - impaired lung function

What is the MOA of irrinitecan?

1. Prodrug - converted to active 7-ethyl-10-hydroxy-camptothecin by a carboxylesterase-converting enzyme (CCE)

2. Topoisomerase I inhibitors

   1. Stabilizing covalent DNA topoisomerase I cleavable complex - prevents DNA replication

   2. Converts into lethal double stranded DNA damage

What is the MOA of doxorubicin on DNA? What is the target?

1. Intercalate into double helical DNA to inhibit DNA/RNA synthesis

2. Prevents replication of rapidly growing cancer cells

   1. Topoisomerase II inhibitors: Anthracyclines

3. Stabilizes the topoisomerase II complex after it has broken the DNA chain

What is the MOA of etoposide?

1. Does not bind directly to DNA

2. Stabilizes a covalent intermediate form of the DNA topiosomerase II complex

What is the MOA of vinblastine?

Mitotic spindle poisons that block the polymerization of tubulins into microtubules

Vinblastine is comprised of 2 multi ringed units:

1. Indole containing (catharanthine)

2. Indoline moiety (vindoline)

MOA of paclitaxel?

Mitotic spindle poisons that block the depolymerization of microtubules into tubulins

What is the MOA of trastuzumab?

1. Hepceptin - Humanized Anti-HER2 Mabs

2. Binds Her2 subdomain IV - inhibits HER2 activation

3. Induces antibody dependent cellular cytotoxicity (ADCC) - destroys cancer

What is the major clinical uses of trastuzumab?

1. Before/after surgery with HER2 + metastatic breast cancer

2. Her2 positive metastatic stomach or gastroesophageal junction cancer

What is the difference between trastuzumab and trastuzumab emtansine?

1. Trastuzumab Emtansine is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (HERCEPTIN)

2. COVALENTLY LINKED to the cytotoxic agent maytansine (DM1)

What two monoclonal antibodies inhibit cancer growth by blocking the epidermal growth factor receptor (EGFR)?

Cetuximab and Pantumumab

Bevacizumab is a monoclonal antibody that slows tumor growth by blocking what?

1. Inhibits VEGF

2. Decreases the blood supply to the tumor and slows tumor growth

What 2 drugs are monoclonal antibodies that target and eliminate B cells by binding to CD20 protein?

1. Rituximab

2. Ofatumumab

Pembrolizumab and nivolumab both function as ____ checkpoint inhibitors by blocking the _____ receptor, a protein on T cells that normally helps prevent T cells from attacking other cells in the body (Cancer cells)

Checkpoint Blockade - Programmed death (PD-1) receptor

Ipilimumab functions as ____ a checkpoint inhibitor by blocking the _____ receptor, a protein on T cells that normally helps prevent T cells from attaching other cells

CTLA-4 inhibitor

Blocks the CTLA-4/B7 interaction

What does bortezomib target?

1. Proteasome inhibitor

2. Interacts with hydroxyl group of the threonine activate site of the 26S proteasome

3. Competitive, yet reversible inhibitor

MOA of Olaparib?

1. PARP inhibitors - treatment for BRCA deficienct cancer

2. This enzyme plays a crucial role in DNA repair

3. PARP inhibitors - accumulation of DNA damage - cell death

List GnRH agonists and antagonist?

1. Agonists: Leuprolide, Goserelin, Triptorelin, Histrelin

2. Antagonist: Degarelix

   1. reduces testosterone levels more quickly

What is the MOA of abiraterone and flutamide?

1. Abiraterone: suppresses production of androgens - inhibits CYp17A1 - decreases testosterone

2. Flutamide: Nonsteroid antiandrogens - antagonist of androgen receptor