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
