Chemotherapeutic Agents 1 Cytotoxic Chemo

Alkylating Agents

• Nitrogen Mustards

• Methylators

• Platinums

Antimetabolites

• Antifolates

• Pyrimidines

• Purines

Alkylating Agents

-Cell-cycle NON-SPECIFIC

-act at multiple phases of cell cycle

-All are electrophilic molecules that covalently modify nucleic

acid bases on DNA

monofunctional

cause single strand DNA breaks

bifunctional

inhibit DNA replication and transcription by cross-linking DNA

Nitrogen Mustards

Cyclophosphamide

Methylators

• Temozolomide

• Dacarbazine

Platinums

Cisplatin

Nitrogen Mustards

-Produce cytotoxicity by forming covalent inter-strand cross-links in DNA. The nitrogen mustard cross-link has been demonstrated to occur in the G-C rich region of DNA.

-Contain two reactive arms:

• Example: CYTOXAN (cyclophosphamide)

Cyclophosphamide

-Oral, prodrug: biotransformation by CYP in liver, oral administration.

-First-pass hepatic metabolism forms active metabolites

Acrolein

-active drug

-by product of cyclophosphamide

-toxic to the bladder epithelium and can lead to hemorrhagic cystitis

co-admin or prophylaxis with the thiol drug MESNA bc it is an acrolein scavenger

what is the solution to the toxic metabolite active drug from cyclophosphamide?

Cyclophosphamide Toxicity

-Common Adverse Events

• Myelosuppression (neutropenia, anemia, thrombocytopenia)

• Fever

• Alopecia

• CINV

• Diarrhea

-Hemorrhagic cystitis

• Inflammation of the bladder mucosa by urinary cyclophosphamide metabolites, (Acrolein). Mitigated with MESNA therapy.

-Cardiotoxicity (can be fatal)

• The syndrome usually presents with severe cardiac failure beginning approximately 10 days after drug administration. It is believed the metabolites of cyclophosphamide are responsible.

• Generally observed with high doses

TEMODAR (temozolomide)

-methylator

-The antitumour activity of the prodrug temozolomide correlates with its accumulation in tumors, where it methylates purines on DNA

-is a an orally administered, second generation prodrug with essentially 100% oral bioavailability. Indicated for glioblastoma multiforme

Temozolomide (TMZ) resistance

• Temozolomide (TMZ) methylates DNA purine bases (adenine and guanine) as part of its mechanism of action as an anticancer drug.

• O6-methylguanine adducts are the most cytotoxic lesions resulting from TMZ treatment, yet are readily repaired (demethylated) by the enzyme O6 -methylguanine-DNA methyltransferase (MGMT)

• The less toxic N7-methylguanine and N3-methyladenine adducts are readily repaired by the base excision repair (BER) system

• This results in the development of acquired resistance contributing to malignant progression, tumor recurrence, and mortality

• The inhibition of PARP blocks BER pathways and increases cytotoxicity of TMZ

Dacarbazine

-used to treat melanoma and Hodgkin's lymphoma. Part of the polychemotherapy regimen:

• ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) used in the first-line treatment of Hodgkin's lymphoma.

• Prodrug—similar to temozolomide

Cisplatin

-identified as an antitumor agent in 1969. Approved for medical use in 1978. Since then, two additional platinum drugs have been FDA approved.

-The chances of a complete cure of testicular and bladder cancer have vastly improved (>99% success) due to cisplatin and other second-generation platinum drugs. Testicular cancer is now largely curable

platinum MOA

The platinum atom of cisplatin binds covalently to DNA bases to form crosslinks

Cisplatin

DNA adducts cause various cellular responses, such as replication arrest, transcription inhibition, cell-cycle arrest, DNA repair and apoptosis

AEs of Cisplatin

-there are over 40 associated AEs

-ototoxicity

-cardiotox

-nephrotox

-haematologic tox

-gastrointestinal tox

-hepatotox

-neurotox

Cisplatin Major AEs

-Nephrotoxicity: The two most common nephrotoxic side effects of cisplatin are acute kidney injury and hypomagnesemia, which is reported to affect up to 90% of cisplatin treated patients. The hypomagnesaemia stems from the damaged kidney's inability to reabsorb magnesium.

• Hydration (The main objective of hydration during cisplatin therapy is to maintain sufficient urine flow, thereby facilitating the drug's elimination from the kidneys and minimizing the risk of kidney damage)

• Magnesium supplementation

-Peripheral Neuropathy

-Nausea and Vomiting

• Antiemetics

-Myelosuppression

Antimetabolites

• Drugs used are counterfeit structures of normal precursor molecules used in DNA synthesis

• Act at the S phase-cell phase specific

-Dihydrofolate Reductase (DHFR) inhibitors

-Pyrimidine analogs

-Purine analogs

What are the 3 main classes of antimetabolites?

Dihydrofolate Reductase (DHFR) Inhibitors

Methotrexate (MTX)

Pyrimidine analogs

• 5-fluorouracil (5-FU)

• Capecitabine

Purine analogs

6-mercaptopurine

Folic acid (folate)

-is an essential dietary factor used for synthesis of purines

-is converted to Dihydrofolate (FH2)and then Tetrahydrofolate (FH4) cofactors which provide single carbon groups for the synthesis of dTMP

high

Competitive inhibitors of DHFR, like methotrexate (MTX), are administered ________ dose and approved for cancers like Acute Lymphoblastic Leukemia (ALL)

• Depletion FH4 in cell → depletion ofdTMP → Inhibition of DNA synthesis

Methotrexate

-cross biological barriers poorly, being highly ionized and generally hydrophilic

-used in high doses in cancer therapy-can also cause very serious, life-threatening AEs highly dependent on the tx duration, age and condition of the pt

-minimal effective concentration and minimal toxic concentration is considerably small and the drug has a very narrow therapeutic window

-Notable toxicities of High Dose are mucositis, myelosuppression, renal failure, liver injury, and neurotoxicity

-Managing HD-MTX toxicities, particularly nephrotoxicity -has been well documented. Avoidance of renal injury and the consecutive risk of impaired clearance is therefore paramount to prevent toxicity

Rescue normal cells from toxicity by providing folinic acid (leucovorin) 24-42 hours after administration of MTX

Problem: MTX has little selectivity for tumor cells, and its effectiveness is limited by toxicity to normal tissue, particularly the gastrointestinal (GI) epithelium and bone marrow.

◼ But, to kill a cancer cell, it must be given in high doses (>500 mg/m2).

What is the solution?

Leucovorin

allows for some purine synthesis to occur in the presence of DHFR inhibition, by MTX, so that DNA replication and RNA transcription processes can proceed in normal cells. Mitigate toxicity

give Bicarb to raise the urine pH from 5 -> 7.5 and the solubility of MTX increases about 20-fold

Urine alkalization has been identified as a crucial aspect of MTX clearance and prevention of renal toxicity. At a urine pH of 5, the solubility of MTX is very low, and it can precipitate within renal tubuli, which induces severe kidney damage with the consequence of acute renal failure. In some cases, this condition will require dialysis. What is the solution?

VORAXAZE (Glucarpidase)

-is a recombinant carboxypeptidase G2 (CPDG2) enzyme which rapidly lowers blood levels of MTX, reducing its concentration to below the threshold for serious toxicity.

◼ It converts MTX to its inactive metabolites, providing an alternative route of MTX elimination to renal clearance during high-dose methotrexate treatment.

◼ It is indicated for the treatment of toxic plasma MTX concentrations (>1 micrometer) in patients with delayed MTX clearance due to impaired renal function, and is supplied as a solution for intravenous administration.

Fluoropyrimidines

a group of cytotoxic anticancer drugs including 5-fluorouracil (5-FU) and its oral prodrug capecitabine (XELODA) have been the backbone of anticancer treatment in a variety of cancers, including breast, colorectal, head and neck, pancreas and gastric cancer, for over 50 years

5-FU and 5-FU oral prodrugs

In metastatic colorectal cancer (mCRC),intravenous ____________ have become the mainstay of systemic treatment since the 1990s.

5-FU

exerts its antitumor effects mainly through the inhibition of thymidylate synthase (TS)

Capecitabine (XELODA)

is a prodrug of 5-FU. But it needs a lot of editing prior to becoming active 5-FU. It requires three enzymatic steps, the last one is really critical (thymidine phosphorylase) for the following reason

17x

Capecitabine has a therapeutic index about _______ that of other 5-FU prodrugs and 5-FU.

anabolism

is the set of metabolic pathways that construct molecules from smaller units

a small fraction (1-5%)

What % of 5-FU is converted intracellularly into the cytotoxic phosphorylated species required to kill cancer cells?

80%

What % of 5-FU is converted to the inactive metabolite by DPD in a pt with 2 copies of functional DPD?

DPYD gene

encodes the enzyme dihydropyrimidinedehydrogenase (DPD) which catalyzes the rate-limiting step in fluoropyrimidine metabolism

PM phenotypes with 5-FU and DPYD genes

are at risk of potentially life-threatening 5-fluorouracil toxicity, such as bone marrow suppression, diarrhea, and neurotoxicity (recall SN-38)

no dose has been proven safe in individuals with absent DPD activity

What did the FDA-apprvbed drug label for 5-FU say about the DPYD gene?

1

What is the activity score of a normal functional allele?

0.5

What is the activity score of a reduced function allele?

0

What is the activity score of a LOF allele?

2

What is the activity score of a DPYD normal metabolizer?

1 or 1.5

What is the activity score of a DPYD IM?

0 or 0.5

What is the activity score of a DPYD PM?

reduce dose by 50%

What is the dose reduction for an activity score of 1 for DPYD IMs?

reduce dose by 25% to 50%

What is the dose reduction for an activity score of 1.5 for DPYD IMs?

avoid use

What is the recommended dosing of 5-FU or Capecitabine for DPYD PM with an activity score of 0.5 to 0?

serious AEs or death may occur in pts with complete DPD deficiency and pts must be genetically tested prior to use

What is now included in the BW of Capecitabine?

Gemcitabine (GEMZAR)

• Single agent of choice for metastatic pancreatic cancer, but used in combination for ovarian, breast, NSCLC.

• Inhibits DNA synthesis; fraudulent nucleoside; converted to nucleotides by sequential phosphorylation to triphosphate.

• The most common adverse reactions for the single agent (≥20%) are nausea/vomiting, myelosuppression.

• It is generally well tolerated but can cause gastrointestinal disturbances, renal impairment, pulmonary toxicity, and influenza-like symptoms.

Thiopurines

-are oral anticancer agent used mainly in the treatment of acutelymphoblastic leukemia (ALL)

-are very useful drugs, but they have a relatively narrow therapeuticindex, with life-threatening myelosuppression as a major toxicity.

-have PGx issues with the drug metabolizing enzyme TPMT

prodrugs

6-mercaptopurine, 6-thioguanine, azathioprine are ____________. Require sequential ribosylation (sugar addition) and phosphorylation by kinases as part of the mechanism of action against cancer cells.

Thiopurine metabolism

-Thiopurine drugs are metabolized by the enzyme Thiopurine methyltransferase (TPMT)

-The methylated metabolites resulting from the TPMT reaction are not active as anticancer agents.

-So, with the "standard dose" of thiopurines, a balance exists that controls levels of thiopurine exposure in the blood.

-TPMT is a drug metabolizing enzyme—its responsible for metabolic clearance of thiopurines.

-If TMPT is not functioning, higher than normal levels of thiopurines are present when given the standard dose.

-So, dose adjustments are required based on TMPT genotypes.

reduced dose by 30-70%

Dosing of Mercaptopurine with heterozygote or IM activity:

reduce dose by 10-fold

Dosing of Mercaptopurine with homozygous variant, mutatnt, low or deficient activity: