Pharmacology II Unit 3 Review

Cancer Treatment Modalitites…

1. Primary Induction Chemotherapy: used for advanced cancers

2. Neoadjuvant Chemotherapy: used for localized cancers which surgery is incomplete effective 

Adjuvant chemotherapy: complementative therapy to early surgery

Cell Cycle Specific anticancer drugs (CCS) Outline

G1 → S Phase: topo II; etoposide; topo I; irinotecan 

S phase: antimetabolites; capecitabine, 5-FU, methotrexate 

G2 phase: Doxorubicin 

M phase: paclitaxel, vincristine

Cell Cycle Non-specific anticancer drugs (CCNS) Outline

Alkylating agents: cyclophosphamide

Platinum analogs: carboplatin, cisplatin

Cancer Chemotherapy Drug Resistance Mechanisms:

Either primary/spontaneous or acquired means of resistance

1. Gene mutations 

1. Increased DNA repair capabilities 

2. Efflux of drug 

3. Production of “scavengers” → neutralize cancer drugs 

4. Altered drug metabolism (decreased activation of pro-drugs, increased deactivation of active drugs) 

5. Immortalization due to telomere lengething…

Alkylating Agents Overview

 Cytotoxic chemotherapy… NON-cell cycle specific 

→ MOA: covalent attachment of alkyl groups to DNA and associated protein 

Interference with DNA leads + DNA lesions to programmed cell death

• Mispairing 

• Ring opening 

• Cross-linking 

cyclophosphamide, platinum agents

Cyclophosphamide

Cyclophosphamide: DNA Alkylating anti-cancer agent

• Pro-drug

• High ORAL bioavail

ADR: 

• Production of Acrolein toxic byproduct → accumulates in bladder; hemorrhagic cystitis 

MESNA co-treatment: complexes with acrolein and incativates it 

Resistance Mechanism…

1. Increased inactivation of drug 

2. Increased DNA repair mechanisms 

3. Decreased PRO-DRUG ACTIVATION

Platinum Alkylating Agents…

Cisplatin and Carboplatin (reduced nephrotoxicity) 

→ MOA: inter and intra-strand cross links attach DNA together → p53 tumor suppressor activation AND cell death 

• IV admin

• ADR: 

  • Ototoxicity  

  • Nephrotoxicity → dose limiting 

  • Nausea/vomiting induced dehydration  

Resistance Mech: p53 mutation 

Doxorubicin/Daunorubicin

Doxorubicin/Daunorubicin (Anthracyclines) → Targets S phase (DNA replication and division) (CCS)

→ MOA: topoisomerase II inhibition, intercalation into DNA helix, O2 radical production, DNA/RNA strand scission leads to cell death 

ADR: heart failure, GI toxicity 

• Doxorubicin can be complexed with dexrazoxane to mitigate free radical formation 

Bleomycin

Bleomycin (Glycopeptide) → Targets G2 phase (CCS)

→ MOA: intercalation of DNA, iron (Fe+) binding, free radical generation; apoptosis 

used for testicular cancer curative agent in combo

ADR: pulmonary fibrosis leads to lifetime dosing consideration 

• inactivated by bleomycin hydrase

Methotrexate

Methotrexate → S phase specific CCS (Antimetabolite chemoTX)

→ MOA: decreases purine precursors by blocking folate conversion

• Competitive inhibitor of dihydrofolate reductase (DHFR)

• Inhibition of BOTH purine and pyrimidine synthesis 

ADR: mucosal ulcers, teratogenic due to folic acid needed for fetus

Polyglutamation for MTX: traps MTX within cancer cell

→ via folic polyglutamate synthase (enhanced activity in cancer cells)

• Decreases lipid solubility and traps MTX in cancer cells

Mechanism of Resistance:

1. Altered DHFR (binding site mutation)

2. Decreased MTX uptake 

3. Decreased Polyglutamation 

Methotrexate Rescue 

“Folinic acid rescue”: MTX administered with Leucovorin (reduced folate) 

→ protects non-tumor cells by providing folate 

5-Fluorouracil 5-FU

Thymidylate Synthase Inhibitor (anti-metabolite chemo) ((CCS S phase))

→ Pro-drug activation into 5-dUMP → inhibition of thymidylate synthase enzyme

• Decreases Base pair produciton therefore decreases DNA replication 

• Inhibition of RNA processing 

• Incorporation into DNA 

Mechanism for Resistance: 

• Decreased pro-drug activation 

• Altered thymidylate synthase enzyme binding site

ADR:

• Mucositis 

• Hand-foot syndrome 

Catabolism of 5-FU:

→ Dihydropyrimidine dehydrogenase (DPYD) = rate limiting step in pyrimidine catabolism

Individuals with decreased DPD are unable to metabolize 5-FU away effectively 

• Toxic levels of 5-FU accumulation 

• Pharmacogenomic testing needed

• Lower 5-FU dose for those with poor DPD function  

Cytarabine (Ara-C)

Cytarabine (Ara-C): purine/pyrimidine analogs 

→ MOA: incorrect substrates for DNA/RNA leads to chain termination during S PHASE (CCS)

• Competitive inhibitor of DNA polymerase 

Activated via deoxycytidine kinase into active form of analog 

Gemcitabine

Gemcitabine: Purine/pyrimidine analogs

→ fluorinated cytidine analog for S-PHASE SPECIFIC CYTOTOXICITY

• Competitive inhibitor of DNA Polymerase; inhibits DNA synthesis 

• Early chain termination 

Azathioprine (AZA)

Purine Metabolism Inhibitors…

Azathioprine (AZA): pro-drug converted to 6-Mercaptopurine → 6-TGNs (S-PHASE CCS)

The drug used hypoxanthin-guanine phosphoribsoy HPRT enzyme for pro-drug activation 

• 6-TGNs incorporated into DNA/RNA and arrest replication → trigger cell death

Resistance: decreased HPRT activity, increased inactivation via TPMT

Allopurinol interferes with azathioprine metabolism → leads to TOXIC accumulation of 6-MP

→ co-administration of 6-MP + allopurinol reduced 6-MP dosing 

Microtubule Polymerization: M-PHASE SPECIFIC CCS

Vincristine/Vinblastine: inhibit polymerization/formation of microtubules; Mitotic Arrest (M)

Vinblastine: myelosuppression, Vincristine: peripheral neuropathy 

• Decreased microtubule stabilization inhibits Mitosis from occurring in dividing cells 

Taxanes: Paclitaxel/Docetaxel: inhibit DE-polymerization of tubules (locks them together) (M)

Abraxane (paclitaxel liposomal re-formulation) decreases hypersensitivity 

Topoisomerase I Inhibitors

M-phase specific CCS

Irinotecan: pro-drug converted into active form SN-38 via Carboxylesterase

→ MOA: inhibition of topo I leads to double strand DNA breaks

ADR: severe GI and diarrhea side effects

Topoisomerase II Inhibitors

Etoposide → accumulation of strand breaks; prevents re-ligation of broken strands 

M-phase arrest

Protein-Kinase Depedent Pathways…

• ErbB family → EGFR, Her2/neu

• Receptor tyrosine superfamily: IGF-1R, VEGF, PDGFR

  • RAS-RAP-MAPK

  • BCR-Abl (non-RTK)

  • PI3K-Akt

EGFR: epidermal growth factor receptor

EGFR: epidermal growth factor receptor

→ increased expression in cancer cells 

• Activation of EGFR cascade → cell proliferation, apoptosis inhibition

Erlotinib: direct EGFR receptor antagonist binds INTRACELLULARLY to TK DOMAINS

→ oral, small molecule, tyrosine kinase inhibitor 

ADR: diarrhea, skin rash, anorexia, hand-foot skin reactions 

Lapatinib: EGFR/HER2 dual inhibitor (tyrosine kinase inhibitor) 

Cetuximab, Trastuzumab → EGFR extracellular biologics mAb

• Directed against EGFR

ADR: infusion reactions, hypomagnesemia

mAb Mechanism of Resistance: mutated KRAS 

→ constitutively activated allowing for EGFR-independent growth of cancer cell

Bcr-Abl + Philadelphia Chromosome…

→ transduction of genetic material from normal chromosome 9 ←→ chromosome 22

• Extended chromosome 22

• Bcr-Abl fusion results in: constitutively ACTIVE Abl TK activity: cancer cell growth for Myelogenous Leukemia 

Tyrosine Kinase Inhibitor FOR Bcr-Abl Kinase…

Imatininb (Gleevec): direct Bcr-Abl kinase

• Binds catalytic pocket and inactives kinase enzyme

• Cancer treatment: kills rapid divide cells 

Resistance Mech: mutation of Bcr-Abl binding domain
→ T315 mutants: steric clash PREVENTs imtainib binding

Bevacizumab

Bevacizumab: binds VEGF and prevents signal cascade for cell growth 

ADRs

• Severe hypertension 

• Risk of bleeding 

• Congestive heart failure 

• Preforation of nasal septum, bowel, stomach 

Sorafenib/Sunitinb

Sorafenib/Sunitinb: VEGF Tyrosine kinase inhibitors (platelet-derived growth factor receptor) 

→ MOA: inhibits ATP binding kinase domain (decreases signal cascade) 

ADRs

• Skin rash 

• Hand-foot syndrome 

• Cardiac dysfunction 

• Proteinuria 

Resistance: mutated FLT3 leads to growth factor-indepdent cell signaling 

Everolimus

Everolimus: Analog of rapamycin…

Antifungal/anti-neoplastic → inhibits MTOR pathway; decreased cell survival 

Proteasome Pathway and Cancer…

Proteasome Pathway and Cancer…

Ubiquitin is needed for cellular degradation of proteins

→ cancer cells deplete ubiquitin levels to evade protein lysis allowing for cell survival 

Proteasome inhibitors: prevent degradation of pro-cell death proteins:

E3 ligase targets, EGFR, p53, cyclin, cyclin-depedent kinases

Bortezomib

Bortezomib: Proteasome inhibitor…

→ prevents degradation of pro-apoptotic proteins 

• Leads to increased misfolded proteins, decreased cell function, and cell death 

ADR: shingles (prophylactic acyclovir), heart failure 

Non-Hodkin’s Lymphoma Neoplastic B cell Target Summation. 

Non-Hodgkin’s Lymphoma: cancer arising from overgrowth of cancerous B-cells in blood 

→ CD20 protein: expressed on surface of normal and malignant B cells

• mAb targeting of CD20 allows for antibody-dependent cell cytotoxicity 

  • Results in short term immune deficiency (due to wiping of both normal and cancerous B-cells)

  • CD20 is NOT expressed on naive, B-cell progenitors allowing for replenishment of B-cells after treatment

CD20 Receptor Antibodies…

→ Rituximab and Obinutozumab

Bind to CD20 on malignant (and normal) B-cells 

• Does not target healthy B-cell precursors….

Rituximab: B-cell CD20 mAb

1. Blocks CD20 signaling 

2. Recruits NK cells

3. Recruits Macrophages

4. Employes complement system 

Resistance: decreased complement activation, decreased CD20 expression 

ADR: neutropenia, fever, and infusion reactions 

Obinutuzumab: CD20 B-cell mAb targeting 

Ibritumomab: CD20 B-cell mAb conjugated with radioactive yttrium-90 to enhance killing of cancer B- cells

PD-1 and PD-L1…

• PD-1: programmed death receptor: expressed on activated immune cells 

• Inhibited when bound to PD-L1

PD-L1: expressed by tumor cell to bind PD-1 and inhibit T-cell killing it

Tumor cells overexpress

PD-L1 to evade destruction via T-cells by PD-1 binding immune suppression

Pembrolizumab and Nivolumab

PD-1 Targeted mAb → block T-cell’s PD-1 from being bound and inactivated by PD-L1 on tumor cell

• Pembrolizumab and Nivolumab

ADR: immune mediated organ inflammation, immune mediated hashimoto’s hypothyroidism 

Ipilimumab

CTLA-4: immune down-regulation receptor expressed on T-cells 

→ cancer cells upregulate CTLA-4 to inhibit immune response 

• Ipilimumab

  • Blocks CTLA-4 expression on tumor cells allowing for cytotoxic T-cell action

CAR-T Cell Chemo Treatment

→ collection of patient’s T cells

• Modifcaiton to express CAR protein → allows targeting of cancer cells

  • Re-infusion into patient who has been conditioned…

Downside: 

• Conditioning chemotherapy 

  • Reduces current T-cell population 

  • Allows for repopulation of modded T-cells

ADR:

Cytokine Release Storm

→ too potent immune response after CAR-T infusion

• Dangerous high fever 

• Drops in blood pressure 

• Treat with steroids to avoid 

Tisagenlecelucel

Tisagenlecelucel: gene therapy

mAb that targets CD19 expressing B-cells

• B-cell lymphoma

• Follicular lymphoma 

ADR:

• cytokine release storm

• Immune effector cell-associated neurotoxicity syndrome