Lectures 10-11: Anti-neoplastics

Methotrexate

Acts during S-Phase of cell cycle

Directly inhibits dihydrofolate reductase (DHFR) to block pyrimidine and purine synthesis

Undergoes modification with multiple glutamates → Traps drug in cells → Blocks additional steps in purine synthesis

Crosses BBB poorly, but does get in at high doses and protects against leukemic meningitis

Renal Elimination

Bone marrow suppression is DLT

Treat with leucovorin, a derivative of tetrahydrofolic acid that doesn’t require DHFR to be activated

Dose-Limiting Toxicity

Maximum Tolerated Dose is the highest dose that can be given with acceptable toxicity

Tumor Lysis Syndrome

Complication of chemotherapy resulting from highly effective treatment of tumors with high proliferation rates or cancers causing poor renal function

Hyperkalemia, hyperphosphatemia, hypocalcemia

Hyperuricemia resulting from purine nucleic acid breakdown → Uric acid nephropathy and acute kidney injury

Allopurinol

Tumor Lysis Syndrome Management

inhibits xanthine oxidase

blocks conversion of purines into uric acid

causes excretion of hypoxanthine, which doesn’t crystallize

Rasburicase

Tumor Lysis Syndrome Management

recombinant urate oxidase

converts uric acid to allantoin, which doesn’t crystallize

5-Fluorouracil

IV (or topically for skin cancers)

Bone marrow suppression is DLT

Acts during S-Phase of the cell cycle

Substitution of FUTP into RNA induces translation defects

DNA Damage

dFUMP inhibits thymidylate synthase to block synthesis

Inhibition requires dFUMP, thymidylate synthase, AND tetrahydrofolate

6-Mercaptopurine Pharmacodynamics

Acts during S-Phase of the cell cycle

Inhibits production of PRPP

Inhibits new dATP and dGTP synthesis by:

Outcompeting salvage pathway substrates for A and G base precursors (HGPRT)

Directly inhibiting synthesis of AMP and GMP

Inserts thio-nucleotides into DNA, inducing excision repair, leading to strand breaks and apoptosis

Inhibits G-proteins causing apoptosis

6-Mercaptopurine Pharmacokinetics and Adverse Effects

Crosses the BBB poorly

Metabolized by two major pathways:

Thiopurine S-methyltransferase

Xanthine Oxidase → Risk with Tumor Lysis Syndrome

Adverse Effect: Bone marrow suppression is DLT

Alkylating Agents

Platinum agents: cisplatin

Nitrogen Mustards: cyclophosphamide

Methylating agents: procarbazine

Alkylating Agents Pharmacodynamics

Cytotoxicity is associated with covalent bonding to DNA bases

modification of guanine preferentially

procarbazine forms bonds with individual bases (1:1 stoichiometry)

cyclophosphamide and cisplatin can form two bonds leading to inter- and intra-strand cross-links

Modified guanines can be PRODUCED in ANY PHASE of the cell cycle, but have GREATEST AFFECT on cells in S-PHASE, because they:

inhibit DNA and RNA polymerases (replication and transcription)

may be deleted, which leads to DNA strand breaks (scission)

pair with thymine (instead of cytosine) during replication introducing more mutations

Alkylating Agents Adverse Effects (associated with rapidly dividing cells)

Bone marrow effects:

depression in all lineages, but immunosuppression is DLT for most of these agents

leukemogenesis (acute nonlymphocytic leukemia)

Mucosal toxicity:

oral ulcerations and intestinal denudation

nausea and vomiting due to stimulation of CRTZ

Hair loss

Reproductive system: amenorrhea, decreased spermatogenesis, and teratogenesis/developmental abnormalities

Alkylating Agents Adverse Effects (associated with slowly dividing or senescent cells)

Neurotoxicities (tinnitus to coma)

Pulmonary fibrosis

Vesication (blistering and erosion):

severe tissue damage that results when the drug gets out of the circulation (extravasation)

Cyclophosphamide

Pro-drug (PO or IV)

Metabolism produces acrolein

eliminated in the blood filtrate and not reabsorbed by kidney

Necrotizing hemorrhagic cystitis associated with high doses

Nephrotoxicity correlates with dose received (children <5yr at increased risk)

Prevented with MESNA (2-mecaptoethane sulfonate sodium): Directly binds acrolein in the bladder

Syndrome of Inappropriate ADH (SIADH): High levels of ADH → resorption of water by collecting ducts → hypo-osmolar hyponatremia

→ cerebral edema (nausea, vomiting, headache, and dizziness)

Muscle Cramping and Spasms

Cisplatin

Administered IV

Not metabolized

Actively secreted by kidneys

acts synergistically with ionizing radiation (radiosensitization due to inhibition of nonhomologous end joining during S-phase

LESS bone marrow suppression

Neurotoxicity: (tinnitus to deafness to high-frequency tones, permanent)

Nephrotoxicity (usual DLT, cumulative)

Amifostine protective: Prodrug converted to active form by alkaline phosphatase in normal cells

Marked nausea and vomiting (5-HT3 and NK-1 antagonists)

Procarbazine

Prodrug (PO)

Crosses the BBB

Leukopenia and thrombocytopenia

WORST of leukemogenic agents (risk of acute leukemia)

MAO Inhibitor (risk of hypertension)

Potentiates sedation (so, don’t use with other sedatives)

Disulfiram-like effects

Bleomycin

binds to DNA → Complexes with iron to generate free radicals → strand breaks and DNA fragmentation (not cell cycle dependent)

Doesn’t cross the BBB

~70% is eliminated unchanged in the urine

Is hydrolyzed in most cells except lung and skin

Adverse Effects:

VERY LITTLE myelosuppression

Pulmonary fibrosis: DLT and cumulative

erythema, hyperpigmentation, hyperkeratosis, ulceration, and Reynaud

Fulminant Reaction – similar to anaphylaxis (hyperthermia, hypotension, and sustained cardiorespiratory collapse)

Headache, Nausea and vomiting

Doxorubicin

acts during ALL PHASES of the cell cycle

combines with IRON to CATALYZE oxygen radical generation → DNA damage and apoptosis and lipid damage of cell membranes and ion leakage

inhibits topoisomerase II to block DNA replication

intercalates into DNA reducing RNA synthesis

IV

reduce dose for hepatic dysfunction

doesn’t cross BBB

Doxorubicin Adverse Reactions

GI toxicity (stomatitis, mucocitis, diarrhea, nausea, and vomiting)

Transient decrease in ejection fraction occurs w/in 24 hrs

thrombocytopenia and neutropenia (DLT)

alopecia

“Pericarditis-Myocarditis Syndrome”: Altered ST-interval and T-waves and Frank CHF with pericardial effusion

Vesication – this is the WORST offender

dilated cardiomyopathy → total dose can be increased with dexrazoxane (iron chelating agent)

Radiation recall reactions: Erythema and desquamation at sites of previous radiation therapy

Vinblastine and Vincristine MOA

bind b-tubulin and block polymerization at the (+) end

Microtubules collapse, because depolymerization outpaces polymerization

Blocks formation of the mitotic spindle during M-phase

Vincristine Adverse Reactions

Neurotoxicity is DLT

Due to effects on axonal microtubules

Reversible

Frequently fatal if injected into CSF

reversible alopecia

colic/constipation

Not strongly myelosuppressive

Vinblastine Adverse Reactions

Myelosuppression is DLT

SIADH

nausea or headache to seizures

alopecia, stomatitis, dermatitis

nausea, vomiting, diarrhea, anorexia

Not strongly neurotoxic

Paclitaxel

bind b-tubulin and stabilize polymerization

Microtubules rigidify, because polymerization outpaces depolymerization

Blocks mitotic spindle dynamics during M-phase

IV

Metabolized by CYP-450

Adverse Effects:

Bone marrow suppression is DLT at low doses

Peripheral (stocking glove) neuropathy is DLT with high doses or prolonged infusions

Hypersensitivity

Mucositis with prolonged or repeated doses

Rare, asymptomatic brady- or tachy-cardias

All-Trans Retinoic Acid

Acute promyelocytic leukemia (APL)

APL is caused by chromosomal translocation leading to fusion of the PML and Retinoic Acid Receptor Alpha (RARA) genes

Fusion protein is a gene repressor that blocks differentiation of promyelocytes

exogenous retinoic acid to overcome the block

Retinoic acid is degraded by CYP3A4

Retinoic Acid Syndrome:

increase in mature neutrophils and cytokines

Causes pleural and pericardial effusions, pulmonary infiltrates w/ dyspnea, fever, altered mental status

Pretreat with dexamethasone

Imatinib

Chronic Myelogenous Leukemia (CML)

Fusion protein results from Philadelphia Chromosome Translocation

inhibits ATP binding by the bcr-abl

Sorafenib

Hepatocellular carcinoma

Hepatitis B virus (HBV) causes hepatocellular carcinomas

Hepatitis B X-gene (HBx) is a viral oncogene that promotes growth factor signaling

inhibits the growth factor VEGFR and PDGFR

inhibits RAF in signaling pathways of these growth factors

Cetuximab

Colon Cancer and Head and Neck Squamous Cell Carcinoma (HNSCC)

Mutations in PI3K and RAS in HNSCC and colon cancer

antibody that binds EFGR and blocks binding of EGF

Rash, itching, anaphalactoid reactions

Headache

Trastuzumab

HER2+ breast cancer and gastric cancers

antibody that binds HER2 and prevents dimerization and activation

Cardiomyopathy

Bevacizumab

VEGF signals to endothelial cells and promotes angiogenesis

binds VEGF to prevent signaling

Vascular damage, thromboembolism, poor healing, hypertension, proteinuria

Asparaginase

Acute Lymphoblastic Leukemia (ALL)

acts at the G1 phase of the cell cycle

IM, SC

Minor effects on bone marrow

Hypersensitivity: pruritus, urticaria, dyspnea, hypotension, vomiting and diarrhea

hepatotoxicity

defective coagulation factor production → coagulation defects and hemorrhagic pancreatitis

hyperglycemia (low insulin production)

Ipilumumab

Antigen presenting cells (APC) use tumor antigens to activate T-cell, which can kill tumor cells

After activation, T-cells begin to express CTLA-4

Activation of CTLA-4 by APC’s downregulated cell killing by T-cells, which turns off their tumor cell killing activity

Ipilumumab blocks CTLA-4, which prevents activation of CTLA-4 and maintains tumor cell killing activity of T-cells

Pembrolizumab and Nivolumab

T-cells express PD-1, which inhibits cell killing when activated

Cancer cells express the ligand for PD-1 (PD-L1), activates PD-1

Pembro and Nivo block activation of PD-1