Anti-Cancer Drugs PMC 2025

Cancer chemotherapy drugs are categorized into what 2 things?

CCS (cell cycle specific) and CCNS (cell cycle non-specific)

CCS drugs are NOT active against what kind of cells?

Resting cells (G0 phase)

CCNS drugs can target what? Unlike CCS drugs:

G0 and cycling cells

Are resting or cycling cells more sensitive to CCNS drugs?

Cycling cells

What kind of cancers are CCS drugs most effective against? Why?

Hematologic and solid tumors because most cells are in the growth phase

What type of cancers are CCNS drugs effective against?

Low growth fraction solid tumors and high growth fraction tumors

All cancer chemotherapy drugs inactive what kind of cells?

Stem cells

Why do chemotherapy drugs not target non-stem cells?

They are considered harmless or sterile

What are our CCS drugs? (8)

1. Antimetabolites

2. Bleomycin

3. Epipodophyllotoxins

4. Taxanes

5. Epothilones

6. Vinca Alkaloids

7. Camptothecins

8. Eribulin

What are the current categories of CCNS drugs? (5)

1. Alkylating agents

2. Anthracylines

3. Dactinomycin

4. Mitomycin

5. Platinum analogs

Resistance to anticancer drugs can be categorized as?

Primary or acquired resistance

Describe primary resistance?

Primarily genetic instability which causes resistance to anticancer drugs during the first use

Describe acquired resistance?

Multi-drug or single drug resistant

Over expression of the MDR1 gene on P-glycoprotein involved in drug efflux

Over expression of the MRP1

What do the MDR1 and MRP1 proteins do?

MDR1: is normal but involves p-glycoprotein for drug efflux using ATP as a transport molecule to expel foreign molecules

MRP1: multidrug resistance protein 1 is part of ATP binding transmembrane transporters. It also acts as an export pump especially with natural product anticancer drugs

How can MDR be reversed?

Administration of calcium channel blockers such as verapamil

Which class of anti-cancer drugs were developed from nitrogen mustard during WW1?

Alkylating agents

What are the sub classes of alkylating agents? (4)

1. Bis-chloro-ethyl-amines

2. Nitrosoureas

3. Aziridines

4. Tetrahydroisoquinolones

What are the current most useful alkylating agents in clinical practice?

1. Cyclophosphamide

2. Mechlorethamine

3. Chlorambucil

4. Carmustine

5. Lomustine

6. Busulfan

7. Lurbinectedin

8. Trabectedin

What are the 3 platinum analogs currently used in clinical practice?

1. Cisplatin

2. Carboplatin

3. Oxaliplatin

T or F?: all platinum analogs have the same general MOA

True

What kind of bonding do alkylating agents exert?

Covalent bonding

Cross linking of alkylating agents involves how many strands of DNA? What does this lead to?

One or both

Intrastrand and interstrand cross-links

What does alkylation of DNA result in?

Miscoding or excision of alkylated residues leading to DNA strand breakage

What cells are most susceptible to alkylating agents and platinum analogs?

Replicating cells (late G1 and S phases)

Do mono or bi cross-linked covalent bonded drugs have less damage?

Mono-covalent bonded

What are the 4 main mechanisms of acquired resistance?

1. Increased ability to repair DNA

2. Decreased cell permeability to the drug

3. Conugation of glutathione which inactives electrophilic drugs

4. Increased glutathione S transferase activity which catalyzes conjugation

What are the most common toxicities of alkylating and platinum analogs?

1. Nausea

2. Vomiting (death of intra-abdominal endothelial cells)

3. Myelosuppression

What are our anti-metabolite cancer drugs? (4)

1. Fluorouracil (5-FU)

2. Pemetrexed

3. Gemcitabine

4. Capecitabine

Do some anti-metabolites need to be bioactivated?

Yes: 5-FU, gemcitabine, and capecitabine

How do anti-metabolites exert cytotoxic effects?

1. Bind to catalytic site of enzyme (compete with normal substrate)

2. Bind to allosteric regulatory site (feedback control)

What are our classes of natural products? (4)

1. Vinca alkaloids 

2. Camptothecins 

3. Taxanes 

4. Epipodophyllotoxins

Which vinca alkaloids are plant alkaloids vs. semisynthetic?

Vinblastine and vincristine are plant alkaloids

Vinorelbine is a semisynthetic vinca alkaloid

What plant are vinca alkaloids derived from?

Periwinkle plant (Vinca rosea)

Do all vinca alkaloids have the same MOA?

Yes

What is the MOA of vinca alkaloids?

Depolymerization of microtubules. Specifically tubulin which terminates assembly. Ultimately stops M phase and interferes with chromosome segregation and the mitotic spindle.

What are the toxicities for each of the three vinca alkaloids?

Vinblastine: N/V, bone marrow suppression, and alopecia 

Vinorelbine: myelosuppression with neutropenia (dose dependent!) 

Vincristine: neurotoxicity (dose dependent!) which includes neuropathy, ataxia, seizures, and coma. some myelosuppression but much more mild. 

What are the 2 epipodophyllotoxins?

Etoposide and Teniposide

Where do the semisynthetic derivatives for epipodophyllotoxins come from?

podophyllotoxins from mayapple root

What is the MOA of epipodophyllotoxins?

Block cell division in the late S-G2 phase, inhibiting topoisomerase II enzyme which breaks the DNA strand.

What are the 4 camptothecins?

Topotecan, Irinotecan, Deruxtecan, and Govitecan

Where do camptothecins come from?

Camptotheca acuminata trees

What is the MOA of camptothecins?

They inhibit the activity of topoisomerase I resulting in DNA damage.

Taxanes are derived from?

Pacific Yew Trees 

What are the three taxanes?

Paclitaxel, docetaxel, cabazitaxel

Which of the taxanes are semisynthetic?

Docetaxel and Cabazitaxel

What is the MOA of taxanes?

Induces mitotic spindle poisons which induces affinity and polymerization and stabilization which leads to arrest of the cells in the G2 and M phase of the cell cycle. This induces apoptosis. 

What are the most widely used cytotoxic anticancer drugs?

Anthracyclines

What are the 5 anthracyclines we need to know?

Daunorubicin 

Doxorubicin 

Idarubicin 

Epirubicin 

Mitoxantrone

What are the four main mechanisms of anthracyclines?

1. Inhibition of topoisomerase II

2. High affinity to DNA through intercalation

3. Binding to cellular membranes

4. Generation of semiquinones and oxygen free radicals

What are the toxicities of anthracylines?

Myelosuppression

Neutropenia

Cardiotoxicity

What are the 2 forms of cardiotoxicity associated with dose-dependent use of anthracyclines?

Acute: first 2-3 days presented as arrhythmias and myocarditis. Usually transient and asymptomatic!

Chronic: dose-dependent dilated cardiomyopathy which causes heart failure produced from free radicals within the myocardium 

How do you reduce the incidence of cardiac toxicity?

decreasing the dose or a continuous infusion

Describe the antidotal effect of dexrazoxane?

removes iron from intracellular cardiac cells via oxygen free radicals so that iron cannot exert it’s effects

What is the antidote for anthracycline cardiotoxicity?

Dexrazoxane (Zinecard or Totect)

What is bleomycin?

A peptide that contains a DNA-binding region and an iron binding domain at opposite ends of the molecule.

Is bleomycin CCS or CSNS?

CCS

What is the MOA of bleomycin?

binds to DNA which causes single and double strand breakage after free radical formation via oxidation of bleomycin-Fe (II) complex leading to inhibition of DNA synthesis

What is the dose-limiting toxicity for bleomycin?

Pulmonary toxicity

Eribulin is a synthetic analog of halichondrin. What is this specifically from?

Pacific marine sponge

What is the ADE of eribulin?

Similar to vinca alkaloids: neutropenia, neuropathies, and GI toxicities 

What is eribulin approved for?

drug-resistant metastatic breast cancer and liposarcoma

What is the MOA of eribulin?

binds to vinca alkaloids bind to B-tubulin and inhibits microtubule assembly. This leads to mitotic inhibition of the G2-M phase 

How is eribulin effective for drug-resistant tumors?

disrupts MDR-mediated P-gp efflux pump