Onco drugs Flashcards
Cyclophosphamide
alkylating agent
Cross-link DNA at guanine
N-7. Require bioactivation by liver. A nitrogen mustard.
USE: Solid tumors, leukemia, lymphomas.
ADVERSE EFFECTS: Myelosuppression; hemorrhagic
cystitis, prevented with
mesna (thiol group of mesna binds toxic metabolites) or N-acetylcysteine.
Mechanism of Action - Forms DNA cross-links, resulting in inhibition of DNA synthesis & function
Toxicity - Acute: (GI)-Nausea & Vomiting
- Delayed: Moderate depression of peripheral blood count {Excessive doses lead to severe bone marrow depression with leukopenia, thrombocytopenia, and bleeding (hemorrhagic cystitis)}
Clinical Applications -
Breast and (Ovarian cancers - Hematologic Malignancies: NHL & CLL - Soft tissue sarcoma - Neuroblastoma - Wilms Tumor - Rhabdomyosarcoma
Procarbazine
Alkylating agent, non classic
Mechanism of action
– Inhibits DNA, RNA, & protein synthesis • Toxicity
– Acute: Nausea and Vomiting
– Delayed: Myelosuppression, CNS toxicity (when used with MAO inhibitors),
– **High risk of secondary malignancy
Oral agent – Cytotoxic drug metabolite acts as Monoamine
Oxidase inhibitor (MAOI) – Adverse drug-drug interactions with:
• Alcohol
• Sympathomimetic amines
• Tricyclic antidepressants
• Anti-histamines
• CNS depressants
• Clinical Applications
– Hodgkin’s lymphoma
– Non-Hodgkins lymphoma
– Brain tumors
– Component of MOPP** regimen
**MOPP- Mechlorethamine, vincristine (Oncovorin®), Procarbazine, Prednisone
Rx: Hodgkins Disease
Platinum based, alkylating agents
• Mechanism of Action
– “stick” to the DN! strands
– **Cytotoxic in ALL stages of cell cycle •
Metabolism: **Renal excretion
• Bind cytoplasmic & nuclear proteins too
• Usually used in combination. Synergize with:
– Other alkylating agents
– Fluoropyrimidines
– Taxanes
Cisplatin
Cisplatin, carboplatin
MECHANISM: Cross-link DNA.
CLINICAL USE Testicular, bladder, ovary, and lung carcinomas.
ADVERSE EFFECTS Nephrotoxicity, peripheral neuropathy, ototoxicity. Prevent nephrotoxicity with amifostine (free
radical scavenger) and chloride (saline) diuresis.
Platinum based, alkylating agents
• Mechanism of Action
– Forms intrastrand & interstrand DNA cross links
– Binds to nuclear and cellular proteins
• Toxicity
– Acute: Nausea & Vomiting (**highly emetogenic)
– Delayed: **Nephrotoxicity, **Ototoxicity, Peripheral sensory, & neuropathy
– **Irreversible nerve dysfunction
• Clinical Applications – Non-small cell & Small cell lung cancers (NSCLC & SCLC) – Head & Neck cancer – Breast cancer – Ovarian cancer – Bladder cancer – GE junction cancer
Oxaliplatin
Platinum based alkylating agent
• Mechanism of Action
– Same as cisplatin and carboplatin but is effective in cells with DNA
Mismatch Repair (MMR) defects
• Toxicity
– Acute:
• Nausea and; Vomiting
• **Neurotoxicity — Laryngo-pharyngeal dysesthesia (Peripheral
sensory neuropathy which can be triggered by cold)
– Delayed: *Neurotoxicity—Peripheral sensory neuropathy which is dose-
dependent (reversible unlike cisplatin), Diarrhea
• Clinical Applications
– **Colorectal Cancer (Component of “FOLFOX” regimen)
– Gastro-esophageal cancer
– Pancreatic cancer
Methotrexate
Folic acid analog – Binds to and inhibits: Reduced folate carrier • DHFR (dihydrofolate reductase) • TS (thymidylate synthase)
• Metabolized in the cell
– Polyglutamate metabolites
– Folylpolyglutamate synthase
-polyglutamates are selectively retained within cancer cells
• Disrupts the folate
metabolic pathway
Pharmacology
• Availability: IV or intrathecal (oral is poorly bioavailable)
• Biologic effects reversed by administration of the reduced folate–**LEUCOVORIN
• Renal excretion
– Dose adjustment with renal insufficiency
– ASA, NSAIDs, & penicillin inhibit renal excretion
• Toxicity
– Mucositis, diarrhea
– Myelosuppression—neutropenia & thrombocytopenia
Four mechanisms of MTX resistance
①Decreased drug transport
②Decreased formation of cytotoxic MTX polyglutamates
③Increased levels of the target enzyme DHFR
④Altered DHFR protein with reduced MTX affinity
5-fluorouracil (5-FU)
Parent form inactive • Activated metabolites include FdUMP (DNAi) and FUTP (RNAi) • FdUMP* inhibits TS – Inhibits DNA synthesis by inducing “thymineless” death
• FdUTP**
– Inhibits DNA synthesis and function
• FUTP***
– Interferes with RNA processing and
translation
Metabolism
– Administered IV; not orally available
– DPD is in saliva
– Short t1/2
– 85% of dose is catabolized by dihydropyridine dehydrogenase (DPD)
– Pharmacogenetics (5%) **If DPD is low or absent (DPD deficiency), toxicity is severe or life-threatening!
• Toxicity
– Myelosuppression
– (GI)-nausea, vomiting, diarrhea, mucositis
– Neurotoxicity
– *Derm—“Hand-foot syndrome” with continuous infusion
Capecitabine
Weber designed this • PRO-PRO-DRUG of 5-FU • **Orally available • Active metabolites are generated in the liver • Metabolites are converted to 5- FU in the tumor – Thymidine phosphorylase
• Toxicity profile reflects continuous
infusion 5-FU particularly:
– *“Hand-foot syndrome” (Fluoro based medicines)
– Diarrhea
– {Not notorious for alopecia - other agents for breast cancer lead to alopecia}
• Clinical use in breast & Colorectal cancer
Cytarabine (Ara-C)
• **S-phase specific antimetabolite • Competitively inhibits DNA polymerases – Blocks DNA synthesis & repair
• Incorporated into DNA
– Blocks chain elongation &
DNA ligation
IV Administration
– Cleared very rapidly; requires almost constant infusion
• Activity
– Hematologic malignancies exclusively
– AML- first-line [combination with idarubicin]
– Liposomal version indicated for lymphomatous meningitis
• Toxicity
– Acute: (GI)-Mucositis, nausea, vomiting, diarrhea
– Chronic: (**Heme)-Myelosuppresion (pancytopenia)
Gemcitabine
①Inhibits DNA polymerases
②Blocks DNA (& RNA) synthesis and repair (ribonucleatide reductase)
③Once incorporated, causes chain
(strand) termination
Activity – Used against **broad range of malignancies: – NSCLC – Pancreatic cancer – Bladder Ca – Ovarian Ca – NHL
• Toxicity – Heme—**Neutropenia – (GI)—Nausea & vomiting in 70% of patients – “flu-like” syndrome – Rare: ***Renal microangiopathy **Hemolytic Uremic Syndrome (HUS)
6-Mercaptopurine (TPMT, allopurinol)
• Inactive parent molecule • Metabolized by HGPRT*
(Hypoxanthine-guanine
phosphoribosyl transferase)
• Inhibits enzymes of Purine
nucleotide synthesis
• Triphosphate forms can be incorporated into RNA and DNA Inactive metabolite
Deficiency of TPMT can lead to increased toxicity
6-MP is deactivated in
reaction catalyzed by
xanthine oxidase
• Allopurinol is often used for
supportive care: – Potent XO inhibitor – Can lead to excessive toxicity
when used with 6-MP – Requires dose reduction
• Pharmacogenetics
– Thiopurine methyl transferase (TPMT) deficiency can result in severe toxicities
• Myelosuppression
• Diarrhea
Vinblastine, vincristine, Vinorelbine
Vinca alkaloids that bind β-tubulin and inhibit its polymerization into microtubules > prevent mitotic spindle formation (M-phase arrest).
Uses: Solid tumors, leukemias,
Hodgkin (vinblastine) and
non-Hodgkin (vincristine)
lymphomas.
Vincristine: neurotoxicity
(areflexia, peripheral neuritis), constipation (including paralytic ileus).
Microtubule dysfunction (M phase) Vinca alkaloids: • Plant-based Alkaloid derivatives • Inhibit microtubule polymerization by binding to b-tubulin to inhibit assembly • Results in mitotic arrest in metaphase
Vinblastine
• Metabolism
Liver cytochrome p450 system
• Toxicity – Nausea, vomiting – Bone marrow suppression – Alopecia – *POTENT VESICANT (blistering agent)
Vincristine
• Active vs. hematologic
malignancies
• Toxicity – ***Neurotoxicity with peripheral neuropathy – **Autonomic system dysfunction • Orthostatic hypotension • Urinary retention • Paralytic ileus – Myelosuppression – ***SIADH
Taxanes
– Paclitaxel + protein bound
Mechanism: Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur).
Clinical use: Ovarian and breast carcinomas.
Adverse effects: Myelosuppression, neuropathy, hypersensitivity. ---------------------------------- • Microtubule spindle poison that enhances microtubule polymerization
• Metabolism: cytochrome
p450 system so that dose
adjustment is necessary
for liver dysfunction
• Clinical use: broad range of
*solid tumors esp. breast
and ovarian cancers &
NSCLC
Paclitaxel: Toxicity
• Acute
– Nausea, vomiting, hypotension
– ***HYPERSENSITIVITY (5%) (in Cremophor based formulations)- can
be prevented with premedication with dexamethasone and diphendydramine
• Delayed
– Myelosuppression
– **(Neurotoxicity), peripheral sensory neuropathy
– ***(Initially single sourced from bark of Pacific Yew tree)
(paclitaxel protein bound or albumin bound)
• Paclitaxel formulated with near nanoparticle size
albumin carrier
• Toxicity
– No paclitaxel related hypersensitivity
– Decreased toxicity overall (vs. paclitaxel)
- FDA approved in:
- Breast Ca
- Non-small Lung Ca
- Pancreatic Ca
Etoposide
Etoposide
MECHANISM Etoposide inhibits topoisomerase II > increase DNA degradation.
CLINICAL USE: Solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas.
ADVERSE EFFECTS: Myelosuppression, alopecia.
- 50% available orally
- Metabolized in the liver and also excreted renally
• Toxicities: – Nausea, vomiting – Hypotension – Myelosuppression – Alopecia
Camptothecins (Topotecan, irinotecan)
Irinotecan, topotecan
MECHANISM Inhibit topoisomerase I and prevent DNA unwinding and replication.
CLINICAL USE Colon cancer (irinotecan); ovarian and small cell lung cancers (topotecan).
ADVERSE EFFECTS Severe myelosuppression, diarrhea.
Results in S phase arrest
Topotecan
• IV infusion
• Renal excretion
• Toxicity – Nausea, vomiting – Alopecia – Bone marrow suppression especially neutropenia
– Approved in Small Cell Lung Cancer
Irinotecan • PRODRUG converted in the liver to SN-38 metabolite – Metabolite is 1000x more potent than irinotecan • Excreted in the bile and feces
• Toxicity – ***********DIARRHEA into a teacan • Early- cholinergic event • Late- 2-10d post treatment, can be severe! – Bone marrow suppression
– First-line drug for CRC (FOLFIRI regimens)
Anthracycline (doxorubicin)
Generate free radicals.
Intercalate in DNA > breaks in DNA > decrease replication.
USE: Solid tumors, leukemias, lymphomas.
ADVERSE EFFECTS: Cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia. *Dexrazoxane (iron chelating agent), used to prevent cardiotoxicity.
Isolated from a soil microbe:
Streptomyces peucetius
Widely used cytotoxic drugs
example doxorubicin (big red)
①Inhibit Topoisomerase II
②High affinity DNA intercalation
– Blocks both DNA & RNA synthesis
③Generate ***semi-quinone free-radicals
– Major mechanism of **cardiotoxicity
④Bind to cell membranes
– Alters fluidity & ion transport
Pharmacology
• IV Administration
• Metabolism: via Liver to active metabolite
• Toxicity
– (Heme)—Myelosuppresion with neutropenia
– (GI)—Mucositis
– **Cardiotoxicity
• Acute (2-3d): arrhythmias and conduction abnormality
• Chronic: **dose-dependent dilated cardiomyopathy - a specific ceiling. (BIG RED)
(>550mg/m2 cumulative—increased risk)
• Iron-chelator Rx can reduce events in high risk patients
– **Dexrazoxane
One of the most important
anti-cancer drugs • Wide Efficacy • Used in combination
therapy (e.g. ABVD*) for
Hodgkins lymphoma
Bleomycin
Bleomycin Induces free radical formation > breaks in DNA strands. USES: Testicular cancer, Hodgkin lymphoma. Pulmonary fibrosis, skin hyperpigmentation. Minimal myelosuppression.
• Glycopeptide antibiotic from Streptomyces verticillus
• Metal binding
• Binds to DNA
– Causes SS and DS breaks – Inhibits DNA synthesis – Lipid peroxidation
• Cell-Cycle specific: **G2 phase arrest
Metabolism
• IV, IM, or SQ infusion
• Renal excretion
• Toxicity
– PULMONARY
Uses: **Testicular cancer
Hodgkin’s, non-Hodgkin’s Lymphoma
Cell cycle specific to the drug classes
Cell cycle specific
Antimetabolite S
Epipodophyllotoxin G2-S
Anti-tumor Antibiotics
G1/S; phase G2
Taxanes M
Vinca Alkaloids M
Anti-microtubule inhibitor M
Bleomycin G2-M
Critzotinib
Crizotinib: (Inhibits ALK (activin receptor-like kinase), ROS1, HGFR and other TKs
• ~4% of NSCLC patients have translocations involving EML4- ALK1 resulting in constitutive kinase activity • Tend to be younger, non-smokers, wild type for EGFR
and RAS
• Indications: –ALK 1 (with companion diagnostic test for ALK) –ROS 1 mutations
