pharm: Chemotherapy part 1

What drug is the alkylating agent that we need to know?

Cyclophosphamide

Cyclophosphamide gets turned into what two metabolites? explain their roles

phosphoramide mustard: cytotoxic metabolite (anti-cancer)

acrolein: not anti-cancer, urotoxic metabolite

What drugs MOA is: alkylation of nucleophilic groups on DNA bases causing abnormal base pairing, cross-linking, strand breakage, miscoding, etc?

cyclophosphamide

What are the 2 resistance mechanisms of cyclophosphamide?

increased aldehyde dehydrogenase (turns to inactive metabolites)

increased glutathione transferase (detox)

What is the takeaway about the therapeutic uses of cyclophosphamide?

it is used for solid tumors, hematologic tumors (liquid/blood tumors), and a potent immunosuppressant (think tx of autoimmune)

What drug’s main adverse effects include:

hemorrhagic cystitis and cardiotoxicities?

cyclophosphamide (acrolein is the inactive metabolite associated)

How can we mitigate the hemorrhagic cystitis adverse effect of cyclophosphamide?

hydration and mesna (they help with the bladder toxicity)

What drug’s MOA:

gets in through the copper pumps, then get into the DNA and form cross-links then bypass the repair mechanisms and eventually trigger apoptosis

the platinum coordination complezes

cisplatin, carboplatin, oxaliplatin

What are the 4 resistance mechanisms for the platinum analogs (cisplatin, carboplatin, and oxaliplatin)

• decreased uptake by copper transporters

• efflux by ATP7A and ATP7B copper transporters

• inactivation: by glutathione

• repair: the tumor can repair the damage it causes so no apoptosis occurs

What is the order for administering taxanes and platinum drugs? why?

adminster taxane before platinum to limit myelosuppression and increase efficacy

T before P

Which one of the platinum anologs is less reactive than the other two and has less toxicity associated (less need for hydration)

Carboplatin

What are the drugs we use to treat advanced colorectal cancer? (3)

FOLFOX: 5-flourouracil, leucovorin, oxaliplatin

FOLFIRI: 5-flourouracil, leucovorin, irinotecan

What is the dose-limiting toxicity of cisplatin?

nephrotoxicity is dose limiting

also: highly emetogenic (vomiting) and is ototoxic

What is the dose-limiting toxicity of carboplatin?

myelosuppression

What is the dose-limiting toxicity of oxaliplatin?

peripheral neuropathy: acute exacerbated by cold or delayed progressive

What drug’s MOA is:

blocks DHFR which decreases FH4 synthesis which reduces synthesis of thymidylate and purine nucleotides needed to make DNA and RNA

also blocks DHFR which causes it to accumulate and cause apoptosis and cell death in the S phase

methotrexate

What are the 5 mechanisms of resistance for methotrexate?

• decreased transport into cells

• increased expression of drug efflux transporter of the MRP class

• altered DHFR with reduced affinity for methotrexate

• increased concentrations of DHFR

• decreased ability to synthesize methotrexate polyglutamates

What drug’s therapeutic uses include: solid and liquid tumors, childhood ALL, autoimmune diseases, and is abortifacient (tubular ectopic pregnancy)

methotrexate

What drug’s adverse effect and therapeutic use include that it is abortifacient?

methotrexate

explain leucuvorin rescue

Leucovorin rescue is a treatment method used to reduce the toxicity of methotrexate by providing an active form of folate that helps normal cells recover after high-dose methotrexate administration, thereby minimizing bone marrow toxicity, hepatotoxicity, and mucositis/stomachitis

• does not reverse neurotoxicity or pulmonary toxicity

leucovorin rescue can be used to decrease what adverse effects? what adverse effects does it not reverse?

works to prevent: bone marrow toxicity, hepatotoxicity, mucositis

does not reverse neurotoxicity or pulmonary toxicity.

What is the oral prodrug of 5-fluoruoracil?

Capecitabine

patients witha complete deficiency of DPD are at risk of severe and excessive toxicity of what drug?

5-fluorouracil

What drug’s MOA is: “thymine-less death”

thymidilate synthesis is inhibitied which causes double strand breaks and RNA processing and functioning is disrupted

5-fluorouracil

What are the 2 mechanisms of resistance for 5-fluoruoracil?

• cancer cells that do not convert 5-FU to 5-dUMP

• altered or increased thymidylate synthase levels

What drug (besides leucovorin) is first line regimen for metastatic colorectal cancer (seen in both FOLFOX and FOLFIRI)

5-fluorouracil

What drug’s toxicities included hand-foot syndrome and cardiac adverse effects

5-fluorouracil

What drug is the only one mentioned that can be used topically for skin cancers?

5-fluorouracil

Explain the efficacy of cytarabine

our normal cells express cytidine deaminase (which breaks down cytarabine into inactive forms) but the enzymes activity is lower in acute myelogenous leukemia (AML) cells so it can target these cancer cells but leave our cells relatively alone

What drug’s MOA is: it gets triphosphorylated and then does competitive inhibition of:

• DNA-polymerase alpha (blocks DNA synthesis)

• DNA-polymerase beta (prevents DNA repair)

• and gets incorporated into the DNA and blocks the chain elengation causes apoptosis

cytarabine

What are the mechanisms of resistance for cytarabine? (3)

primary: loss of deoxycytidine kinase so less conversion to its active form

decreased transport

increased deactivation (increased cytidine deaminase)

explain the enzyme that makes cytarabine into its active form and the one that makes it go to its inactive form

deoxycytidine kinase: active form

cytidine deaminase: inactive form

What is the drug of choice for acute myelogenous leukemia and has no effect on solid tumors?

cytarabine

What drug’s toxicities include cerebellar and cerebral toxicity?

cytarabine

What drug’s MOA is:

it gets converted to TIMP which inhibits de novo purine neucleotide synthesis and also gets incorporated into the DNA and causes strand breaks and base mispairing

6-mercaptopurine

What drug can have increased toxicity in TPMT slow metabolizers?

6-mercaptopurine

What drug has known drug interactions with the xanthine oxidase inhibitors (think allopurinol) and can increase risk of toxicity?

6-mercaptopurine

it shunts the 6-MP to formation of the more toxic metabolite

What drug’s therapeutic uses include acute lymphoblastic leukemia and has potent T cell suppression so its used for tx of crohn’s disease

6-mercaptopurine

What drug’s turn your urine red?

anthracycilnes: we know doxorubicin

What drug’s MOA is:

topoisomerase II inhibition (apoptosis), intercalation in the DNA (DNA strand scission), and causes free radical formation (strand scission and damage to proteins and membranes)

doxorubicin

What drug’s adverse effects include: neurotoxicity, extravasation, radiation recall, and most distinctly: cardiotoxicity (pericarditis-myocarditis syndrome leadings to acute left ventricular failure)

doxorubicin

What should we know about the adminitration of anthracyclines (doxorubicin) and the taxanes?

the anthracycline (doxorubicin) should be administered before the taxane

“A before T”

What drug has a contraindication for being administered intrathecally?

vincristine

What drugs MOA is:

inhibition of microtubule polymerization which arrests the cell in metaphase

vincristine

What drug is the treatment of choice to induce remission in childhood leukemia (can also be used for adult and pediatric lymphomeas and solid tumors)?

vincristine

What drug’s toxicities include neurotoxicity (dose limiting) and constipation (which is interesting becuase normally we see diarrhea)

vincristine

What drug has non-linear clearance?

paclitaxel

What drug’s MOA is:

stablizes the beta-tubulin and prevents microtubule disassembly leading to defects in mitotic spindle assembly

paclitaxel and docetaxel (The taxanes)

What are the dose limiting toxicities of paclitaxel and docetaxel?

myelosupression with neutropenia and peripheral neuropathy (glove-stocking)

What are the 2 mechanisms of resistance for paclitaxel and docetaxel?

increased expression of MDR genes (multi-drug resistant genes)

mutations in the beta-tubulin

explain the two forms of irinotecan

closed ring: active

open ring: inactive

a deficiency in UGT1A1 can lead to what?

increased toxicity from irinotecan due to impaired metabolism of the drug

What drug’s MOA:

binds to topoisomerase and DNA strand resealing is prevented and single strand breaks accumulate leading to irreversible damage and arrest in the S phase leading to cell death

Irinotecan

What are the two mechanisms of resistance for irinotecan?

• increased drug efflux

• alterations in topoisomerase I

What drug is combined with leucovorin and 5-fluoruoracil to treat colorectal cancer as FOLFIRI?

Irinotecan

What are the two dose limiting adverse effects of irinotecan?

bone marrow suppression and diarrhea

What is the dose-limiting toxicity of etoposide?

myelosuprresion

Wha drug’s MOA is:

inhibition of topoisomerase II (prevents resealing of double-strand breaks) and accumulation of breaks that leads to arrest and apoptosis

cell cycle arrest in late S and G2 phase

Etoposide

What are the 3 resistance mechanisms of etoposide?

efflux

topoisomerase II alterations

alterations in p53 tumor suppressor gene

What is the difference between the mechanisms of action of the vinca alkaloids (vincristine) and the taxanes (paclitaxel and docetaxel)?

vinca alkaloids: inhibiti polymersization in microtubules

taxanes: stabilize the microtubules and prevent depolymerization

both suprress spindle microtubule function