Alkylating Agents And Antimetabolites

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4 common toxicities of Alkylators

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Myelosuppression is the primary dose limiting toxicity (neutropenia, anemia, thrombocytopenia. )
GI: N/V/D MUCOSITIS
INFERTILITY
Secondary Malignancy

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Mechlorethamine: MOA and SE

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MOA: aziridium ion atttacked by N7 G
SE: VESICANT

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Cyclophosphamide

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Turns into phosphorabmide and acrolein: HEMORRHAGIC CYSTITIS
SIADH
Cardiotoxicity
Interstitial Pulm. Fibrosis

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Ifosphamide and its rescue agent

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Neurologic toxicity from chloroacetaldehyde
Nephrotoxicity
Hemorrhagic cystitis: GIVE MESNA

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Melphalan

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Delayed N/V Mucositits

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Bendamustine

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Mechlorethamine derivatiteve: N/V fever, Myelosuppression; rare hypersensitivity.
MUSTY= N/V

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Chlorambucil

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hyper uricemia

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2 highly lipophilic Nitrosureas

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Carmustine: (rare: interstitial lung disease, nephritis), phelibits N/V

LOMUSTINE:

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Busulfan and its 3 tox

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Pulmonary fibrosis with chronic low doses, Seizures (use Phenytoin), VOD

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Cisplatin

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Nephrotoxicity and electrolyte wasting
Peripheral neuropathy
Cumulative OTOtoxicity
Always N/V

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Carboplatin

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less toxic than Cisplatin. Dose limiting Myelosuppression like other alkylators.
Delayed hypersensitivity 6-7days

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Oxaliplatin

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Peripheral neuropathy

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Temozolamide

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Triazene: mild elevation in LFTs, photosensitivity.

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6-MP (hypoxanthie) MOA/SE
THIOGUANINE

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MOA: inhibits PRPPamidotransferase, inhibiting first committed step in de novo purine synthesis. Also converted into triphosphate and incorporated into RNA and DNA
SE:
Leukopenia, thrombocytopenia, LIVER toxicity

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Fludarabine

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Depeletes CD4 adn CD8 T cells
Increased infection, parastheisas, fever

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Cladribine and Clofarabine MOA

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Adenosine analogs, inhibit Ribonucleotide reductase and DNAP

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Cladribine SE

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Mild bone marrow depression

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Clofarabine SE

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Hepatotoxcity, capillary leak, tachycardia, hand foot

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Nelarabine MOA/SE

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incorporated into DNA, inhibits synthesis:
Neurotoxicity, Malaise, fatigue

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Pentostatin

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INH adenosine deaminaase, accumulation of dexocyadenosine and dATP which is toxic to lymphocytes

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Pentostatin SE

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myelosuppression and immunosuppression (cytotoxic to lymphocytes)

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Cytarabine

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araCTP: inhibits DNAP, incorporated, NO effect on RNA
SE: neuro, CONJUNCTIVITIS, . Myelosuppression is main toxicity

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Gemcitabine

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Its a gem, its does all three:
INH r. reductase, INH DNAPs, Incorporated into DNA

SE: THROMBOCYTOPENIA, flu like Sx

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5-FU

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FdUMP binds thymidylate synthetase decreases DNA synthesis and repair. Leucovorin Enhances FU; incorporated into DNA/RNA (IV bolus mech)

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5-FU IV bolus SE

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leuco/thrombocytopenia, anemia, Mucositis, photosensitivity

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5-FU continuous IV OR capecitabine (oral prodrug)

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hand foot and diarrhea (+mucositis, photosensitivity)

(use your HAND to say FU)

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Methotrexate MOA

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Folic acid analogue:
INH DHFR decreases cofactors needed for purine and thymidylate synthesis. depletes THF pools

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Methotrexate SE

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Myelosuppression, mucosistis, NEPHROTOX (can have crystalline deposits, need alkaline urine)
Hepatotox: regardless of dose
Neurotox: encephalopathy
N/V

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Methothrexate Rescue

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leucovorin

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Pemetrexed

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folic acid analogue INH:
TS, DHRR, GARFT, AICARFT.
Need premeds: Folic acid, B12

Premeds are competitive, they inhibit everything

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Pemetrexed SE

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skin rash: Dexamethasone
fatigue

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Pralatrexate

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better affinity than MTX
SE: thrombocytopenia>neutropenia, LFT elevations

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HU

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inh: ribonucleotide reductase
Neutrophil suppression

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L-asparaginase

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Hypersensitivity, change in clotting factors, pancreatitis (decreased protein production), hepatotoxicity

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Treatment for Anemia

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RBCs least affected but can give Erythropoietin and darbepoetin; but increased mortality!

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TX for Neutropenia

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most affected
filgrastim, sargramostim (GMCSF)

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Tx for Thrombocytopenia

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Oprelvekin (IL-11) Platelet GF, rarely used

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Tx for Mucositis

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follows progression of ANC, once ANC recovers, mucositis will resolve
Prevention: PALIFERMIN (KGF results in proliferation/migration of epitheilal cells); may stimulate tumor growth

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Tx for Vesicant Extravasation

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Draw back
Cold compress (warm for Vinca)
NaThiosulfate (mustards)
Hylauronidase (vinca)

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Tx TLS

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Hypocalcemia, Acute renal failure, Hyper PO4/K?Uricemia

IV hydration, Rasburicase/'Allopurinol
not alkalinization (unless metabolic acidosis is present)

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Tx for CINV (4 types)

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5HT3 blockers (setrons)
NK-1 inhibitors (aprepitant)
DA antagonists (prochlorperazine, metoclopramide)
Steroids

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Tx for Anticipatory CINV

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Bendodiazapenes