Antineoplastics Flashcards
Methotrexate, Pemetrexed, and Pralatrexate
Class: Folate Analogs
MOA: Competitive inhibition of DHFR, Competitive inhibition of folate dependent enzymes of purine synthesis.
Must have glutamates added by tumor cells
Resistance:
- Increased DHFR, -decreased DHFR affinity
- Decreased polygluatmination
- Decreased folate carrier expression.
PK: Oral for low doses, IV for high doses or intrathecal (overdose common w/ this method)
90% excreted in urine –> give w/ bicarb
Interactions: pharmacokinetic w/ NSAIDS (decrease in renal blood flow(, cisplatin (nephrotoxic), apirin (weak acid)
Therapeutic uses: Broad spectrum, solid tumors
Toxicity: cytotoxic, mocositis and myelosuppression peak at 5-10 days, pneumonitis, hepatotoxicity, abortifacean
Notes:
Leucovorin given w/MTX–>reduced form of folate that allows normal tissue to bypass inhibition of DHFR. –>allows for increased dose of MTX to be used CANNOT BE GIVEN INTRATHECALLY = FATAL
Increased susceptibility when cancer has higher number of folate receptor.
5-FU, Capectiabine, Cytarabine, Gemicitabine
Class: Pyrimidine Analogs
MOA:
- Capecitabine converted to 5-FU in cancer cells
- 5-FU cannot be Methylated by Thymidylate Synthase–>sustained inhibition –>decreased dTMP production
- Also inserted into DNA–>strand breaks
Resistance:
- Changes to Thymidylate Synthase
- Decrease in Pyrimidine monophosphate kinase–>decreased activation of Prodrug
PK:
- 5-FU Given IV (limited oral availability–>gut has high levels of dihydropyrimidine dehydrogenase)
- 5-FU 80% hepatic metabolism and 20% renal excretion
- Capecitabine given orally
- Converted to 5-FU –>1st 2 steps in liver. 3rd = Thymidine phosphorylase (overexpressed in cancer cells)
Theapeutic Uses:
- Given w/MTX
- Colorectal cancer most commonly
- Ovarian & Breast Cancer
AE-
Primary effects = Myelosuppression & GI upset –> peaks @ 9-14 days
Can cause acute cerebellar syndrome–>somnolence, Ataxia, unsteady gait, slurred speech & nystagmus
occurs weeks to months after Tx
Alopecia/dermatitis (hand foot syndrome)’
Can cause radiation recall reaction
Notes: Leucovorin–>increased 5-FU binding to Thymidylate Synthase –>increased half life
Cancer cells have increased sensitivity if underexpressed dihydropyrimidine dehydrogenase (feedback inhibition of TS).
6-Mercaptopurine and 6 Thioguanine
MOA: Block Guanyl kinase causing an increase in IMP and GMP This causes as “psuedofeedback inhibition” or PRPS, GPAT and HGPRT.
Net result is an inhibition of purine nucleotide interconversion decreasing intracellular guanine. Interferes w/ DNA/RNA.
Resistance: Changes in PNP/HGPRT (Decreased HGPRT causes decreased activation of drugs), Increased rates of degradation.
PK:Orally available, must be activated by HGPRT, 6-MP = 2 metabolic liver pathways
Interactions: 6-TG CAN be given w/ allopurinol. 6-MP doses must be decreased 25% w/ allopurinol usage.
Toxicity: Tumor lysis syndrome –> sudden rapid death of millions of cells (esp. leukemia/lymphoma). Causes electrolyte/metabolic disturbances. Can be life threatening. Treat w/ allopurinol.
Cytarabine (Ara-C)
Class: Antimetabolites
MOA: Pyrimidine analog. Mimics CDP/CTP –> incorporated into DNA then blocks DNA pol a. Also inhibits Ribonucleotide reductase.
Gemcitabine
MOA: Inhibits Ribonucleotide reductase and is also a cytosine analog.
Hydroxyurea
MOA: Inhibits ribonucleotide reductase, and synchronizes cells in radiation sensitive phase of cell cycle.
Also a Tx for sickle cell –> increases expression of fetal Hg –> Hgy
Can cause radiation recall reaction
Alkylating agents (general)
MOA: Activated (become electrophilic), Mechlorethamine intravascularly activated by H2O. Nucleophilic attack of DNA –> crosslinking miscoding of bases, DNA strand breaks. CCNS (primary toxicity in G1 and S Phase)
Resistance: Increased nucleophilic substance production (glutathione), increased DNA repair, Decreased activation, MDR is possible.
PK: activation rate depends on substance
Therapeutic uses: Most commonly used group
Toxicity: myleosuppression, severe nausea and vomiting, strong blistering (unless oral), immune suppression, carcinogenesis, mutatgenesis. Side effects are greatest for mechlorethamine.
Notes: Selective toxicity –> DNA damage activates p53 which is mutated in most cancers (no DNA repair)
Mechloethamine
First alkylating agent (nitrogen mustard) made. Not used much any more, but can see secondary cancers caused by it.
PK: IV w/ rapid activation.
Therupeutic uses: Hodgkins
Toxicity: potent vesicant, highly emetic
Notes: Tx extravasation w/ sodium thiosulfate
Cyclophosphamide/Isophosphamide
MOA: Alkylating agent (Nitrogen mustard)
PK: Oral –> CYP450 activation
Uses: Hodgkins, and Breast Cancer
Toxicity: Hemorrhagic cystitis (caused by acrolein which is blocked by MESNA) , Heart and liver toxicity, Isophosphamide = most neurotoxic.
Cisplatin/Carboplatin/Oxoplatin
Cross linking agent (platinums)
Uses: Testicular Cancer, many solid cancers
Toxicity: Most emetic (specific class of anti-emetics made for tx it), kidney, ototoxic, cardiotoxic, peripheral neurophathy
Notes: Hydration w/ saline injections + antiemetics needed
Carmustine (BCNU)/Lomustine
MOA: Alkylating agents (Nitrosureas)
PK: highly lipid soluble (cross BBB)
Therapeutic uses: Brain tumors
Toxicity: Lung/Liver toxicity
Temozolamide
MOA: Alkylating agents
PK: highly lipid soluble (cross BBB), Oral but no liver activation needed
Therapeutic uses: Brain tumors
Toxicity: Lung/Liver toxicity
Chlorambucil
MOA: Alkylating Agent (Nitrogen Mustard)
PK: Oral–> activated by liver
Toxicity: Lung toxicity
Melphalan
MOA: Alkylating Agent
PK: Oral
Thearpeutic Use: Multiple Myeloma
Toxicity: Lung toxicity
Busulfan
MOA: Alkylating agent
PK: Oral
Uses: CML
Toxicities: “Busulfan Tan” = Hyperpigmentation, lung/liver toxicity
Decarbazine
MOA: Alkylating agent
Uses: Hodgkins
Activated by CYP 450
Doxorubicin, Daunorubicin, Epirubicin, Edarubicin, Mitaxantone
Class: Intercalating agent (Anthracyclin Antibiotics)
MOA: Primary = intercalation of major groove leading to inhibition of TOPO II, strand breaks, and chromatid exchange.
Secondary = Alteration of membrane fluidity
Superoxide anion radical formation via CYP450 enzymes
Resistance: Decreased accumulation via an increase in P glycoprotein (MDR), decreased TOPO II activity, Increased glutathione peroxidase activity leading to decreased free radical DNA damage
PK: IV (vesicant), Eliminated via metabolic conversion and biliary excretion
Therapeutic uses: Doxo = boradest spectrum available. 2 Hodgkins regimens. Mandatory for Breast Cancer regimens.
Toxicities: Cardiomyopathy: acute = elevated HR, conduction abnormalities, and arrhythmias, Delayed = non reversible CHF (max dose that when reached must switch drugs); extravasation –> vesicant necrosis; cytotoxic effects; radiation recall reaction (blistering/desquamation at sight of previous radiation); Hand and foot syndrome; red urine (rubro –> not bloody); mitoxantrone = blue urine, sclera, etc
Notes: CCNS (mostly S phase action leading to G2 death.
Class: Intercalating agent (anthracyclin antibiotics)
Bleomycin
Class: Antibiotics
MOA: creates free radicals which cut DNA into many pieces (Bleomycin = blows up DNA)
Accumulaiton of cells in G2 w/ chromosomal aberations
Resistance: Increased hydrolase activity; increased DNA repair
Uses: Testicular cancer, lymphomas, SCC, Many regimens due to unique MOA
Toxicity: Hypersensitivity; GI upset; lung (pulmonary fibrosis) and skin lack hydrolase that degrades, alopecia, edema of hands
Etoposide
Class: Plant alkaloids.
MOA: complexes w/ TOPO II and remains bound preventing DNA repari/ replicaiton
Resistance: Decreased accumulation via increase in P-Glycoprotein, change in TOPO II, Decreased apoptosis due to p53 mutation
Toxicities: N/V; CV (hypotension/EKG abnormalities), Alopecia, Leukopenia
Irinotecan/Topotecan
Class: Plant Alkaloids
MOA: Inhibits TOPO I
Resistance: Decreased activation, decreased accumulation via increase in P-glycoprotein,
PK: Prodrugs; irinotecan eliminated by the Liver, excreted in Bile/Feces; Tropotecan metabolized and renally excreted
Uses: Metastatic CRC
Toxicity: Myelosuppression, Diarrhea: early –> + cholinergic sx, late –> prolonged dehydration, electrolyte imbalances and sepsis
Notes: Tx Early Diarrhea w/ atropine; Tx late diarrhea w/ loperamide
Procarbazine
MOA: Alkylating but more effects on RNA and protein synthesis than others. Causes strand breaks more than other alkylating agents.
PK: metabolically activated spontaneously or via cyp450 enzymes
Increased risk for leukemia
ATRA (All Trans Retinoic Acid)
Used to treat M3 subtype of AML due to cells (faggot cells) having mutated retinoic acid receptor.
Very effective; important dx and rx combo to prevent DIC caused by M3 AML if treated classically.
Leucovorin
Rescues normal cells in MTX treatment. Folate analog that doesn’t require DHFR.
Normal cells can use at higher rates than cancer cells.
Preferentially taken up via reduced folate carrier (rfc) protein (expressed at lower rates in cancer cells) vs. folate receptor.
Allows us to give very high doses of MTX.
Also increases binding affinity and half-life of 5-FU for Thymidylate synthase
Glucarpidase
Enzyme that degrades MTX. Given w/ MTX overdose or w/ kidney insufficiency.
Mitomycin
Cross linking antibiotic.
Selectivity: Need reduction reaction to activate (more likely in hypoxic cancer cells)
Resistance via increased trapping agents and increased DNA repair
Toxicity: lung toxicity (in less than 10% but fatal in 50%); kidney toxicity.
MESNA
Adjunct given w/ cyclophosphamide which blocks acrolein preventing hemorrhagic cystitis.
