Chemotherapy Pharmacology

What naming suffix indicates a monoclonal antibody?

-mab

What naming suffix indicates a small‑molecule inhibitor?

-inib / -ilib / -isib

What naming suffix indicates a platinum alkylating agent?

-platin

What naming suffix indicates an anthracycline?

-rubicin

What naming suffix indicates a topoisomerase I inhibitor?

-tecan

What naming suffix indicates an antitumor antibiotic?

-mycin

Mechanism of monoclonal antibodies

Direct tumor killing, Antibody dependent cellular cytotoxicity, complement mediated lysis, apoptosis

Mechanism of tyrosine kinase inhibitors

Block phosphorylation signaling → ↓ proliferation+differentiation, ↑ apoptosis

Example of Extracellular targeted therapy? Intracellular?

Mabs target outside of cell; TKIs target inside of cell

Methotrexate mechanism

Inhibits DHFR → ↓ THF → ↓ purine & thymidylate synthesis → ↓ DNA synthesis

Methotrexate major toxicities

Nephrotoxicity, myelosuppression, mucositis, hepatotoxicity, neurotoxicity

Methotrexate rescue agent

Leucovorin (folinic acid)»gets directly converted into THF(doesnt need DHFR) allowing for resumption of DNA synthesis. Used for >MTX 1gram/m²

Rapid rescue with glucarpidase which actively cleaves MTX

Methotrexate risk factors for toxicity

Renal dysfunction, acidic urine, NSAIDs, PPIs, sulfonamides, 3rd‑space fluids

Glucarpidase mechanism and use

Cleaves MTX → inactive metabolites cleared hepatically. Used for rapid MTX toxicity

Fluorouracil (5‑FU) mechanism

Converted to FdUMP → inhibits thymidylate synthase → ↓ thymidine → ↓ DNA synthesis

Why give leucovorin with 5‑FU?

Stabilizes FdUMP‑TS complex → ↑ cytotoxicity

Flurouracil (5‑FU) major toxicities

Myelosuppression, mucositis, hand‑foot syndrome, diarrhea, cardiotoxicity (rare)

G‑CSF timing rule

Give ≥24h after chemo and ≥10 days before next cycle

6‑MP mechanism

Inhibits de novo purine synthesis

6‑MP toxicity

Myelosuppression, hepatotoxicity

6‑MP pharmacogenomic warning

TPMT deficiency → severe toxicity

Hydroxyurea mechanism

Inhibits ribonucleotide reductase»dec hematopoesis, inc HbF

Hydroxyurea uses

CML blast crisis, sickle cell disease

Hydroxyurea toxicity

Myelosuppression

Alkylating agent mechanism

DNA crosslinking which prevents strands from unwinding → strand breaks → apoptosis

Cyclophosphamide/ifosfamide(alkylating agents) toxic metabolite

Acrolein

Acrolein (biproduct of alkylating agents) toxicity

Hemorrhagic cystitis

Hemorrhagic cystitis prevention

Vigorous hydration + MESNA

MESNA mechanism

Binds acrolein in bladder → forms nontoxic compound to prevent hemmorhagic cystitis

Cyclophosphamide/Ifosfamide toxicities

Hemorrhagic cystitis, SIADH, delayed N/V, Neurotoxicity, Fanconi syndrome

MESNA Indication (drugs)

Cyclophoshamide >1g/m² AND/OR Ifosfamide at ANY dose(bc it produces high levels of acrolein)

Cisplatin (Platinum) major toxicities + prevention

Nephrotoxicity, ototoxicity, neuropathy, severe N/V. Prevent with hydration (ciSPLATin=>bc N/V)

Oxaliplatin major toxicity

Cold‑induced peripheral neuropathy

Platinum hypersensitivity mechanism

IgE‑mediated, ↑ risk after >6 doses

Alkylating agent categories

Phosphoramides mustards: Cyclophosphamide + Ifosfamide

Platinums: Cisplatin, Carboplatin, Oxaliplatin

Topoisomerase I inhibitors Ex’s

Irinotecan, topotecan

Topoisomerase Inhibitors MOA

prevents DNA strand break repair after topoisomerases unwind the strand

Camptothecins (Topoisomerase Inhibitor 1’s) acute diarrhea treatment

Atropine + loperamide for chronic

Topoisomerase II inhibitors»Anthracyclines (end in rubicin)

Anthracyclines (doxo, daunorubicin, idarubicin, epirubicin), etoposide

Antitumor Antibiotics MOA and Ex

DNA strand breakage. Ex: Bleomycin(watch for pulmonary toxicity), Dactinomycin, Mitomycin

Anthracycline mechanism

Inhibit topo II + generate free radicals → DNA damage

Anthracycline(topoisomerase 2 inhibitors) toxicities!!

Cardiotoxicity, extravasation injury, myelosuppression, red urine, mucositis

Anthracycline cardiotoxicity mechanism

Free radical formation → lipid, protein and DNA damge→myocyte damage/death

Anthracycline cardioprotective agent

Dexrazoxane- inhibits iron dependent free radical formation

or using liposomal delivery of anthracycline

Anthracycline extravasation treatment

Dexrazoxane + cold compress

Vinca alkaloid mechanism

Prevent microtubule assembly → mitotic arrest

Vinca alkaloid fatal administration route!!!!!!

Intrathecal (fatal)

VinCristine Uses + major toxicity

Uses: Childhood leukemias, Childhood tumors, hodgkins

Toxicity: CNS toxicity (therefore dont’ do it intrathecally), Peripheral neuropathy (marrow‑sparing)

VinBlastine and VinorelBine uses and major toxicity

Uses: hodgkins, lymphomas, Breast, testicular

Toxicities: Bone marrow suppression

Taxane mechanism

Stabilize microtubules → prevent disassembly(act like concrete) → mitotic arrest

Taxane toxicities

Neuropathy, mucositis, myelosuppression, hypersensitivity, alopecia

Proteasome inhibitor examples

Bortezomib, carfilzomib

Bortezomib major toxicity

Peripheral neuropathy (less with SQ route)

Carfilzomib(proteasome inhibitor) major toxicity

Cardiac failure, pulmonary hypertension

Tamoxifen mechanism

Anti‑estrogen in breast, pro‑estrogen in uterus

Rituximab target

CD20

Rituximab toxicities

Infusion reactions, Tumor Lysis Syndrome, infections

Tumor lysis syndrome lab abnormalities

↑ K, ↑ phosphate, ↑ uric acid

Tumor Lysis Syndrome treatment

Fluids, allopurinol(reduces uric acid systemically), rasburicase(cleaves uric acid)

Alemtuzumab target

CD52»targets B and T lymphocytes

Epidermal Growth Factor receptor(EGFR-1) inhibitor toxicities

Skin rash, diarrhea, Interstitial Lung Disease, hypomagnesemia, GI

EGFR2/HER2 inhibitor toxicities

Reversible cardiotoxicity, infusion rxn

BRAF inhibitor class toxicities and used for

New malignancies, uveitis, photosensitivity, QT prolongation

VEGF inhibitor mechanism + example

Blocks angiogenesis. Bevacizumab

VEGF inhibitor toxicities

HTN, bleeding, thrombosis, impaired wound healing

Imatinib targets

Philadelpia Chromosome: BCR‑ABL, c‑KIT, PDGFR. It is a TKI

Imatinib uses + AE

CML, Gastrointestinal Stromal Tumors (GIST). AE: N/V/D, bleed, pancreatitis

Immunotherapy Mechanism (2+) and Toxicity

CTLA4 inhibition(normally silences immune system but when inhibited T cells kill), PDL1 inhibition(normally inhibits programmed cell death, but once inhibited will let T cells kill)

Toxicity: Autoimmune like toxicity