elsaid - alkylating agents, platinum compounds, and antimetabolites

alkylating agents MOA

reacts with N7 guanine and forms alkylated base or a cross-link

alkylating agents:

• nitrogen mustards

• mechlorethamine

• chorambucil

• melphalan

• cyclophosphamide

• ifosfamide

alkylating agents:

• nitosureas

• carmustine

• lomustine

alkylating agents:

• alkylsulfonates

busulan

alkylating agents:

• triazenes

• procarbazine

• dacarbazine

• temozolomide

cyclophosphamide

• alkylating agent

• main organ-specific toxicity is hemorrhagic cystitis due to generation of Acrolein

  • Acrolein reacts with bladder tissue proteins and results in cell death and inflammation

ifosfamide

• alkylating agent

• generates acrolein and may cause hemorrhagic cystitis

• generates chlordacetaldehyde

  • the generation of this metabolic byproduct causes renal tubular cell toxicity characteristic of ifosfamide

mesna (2-mercaptoethane sulfonate sodium)

• cytoprotective agents

• MOA:

  • detoxification of Acrolein via chemically reacting with the toxic metabolite

• use:

  • to reduce risk of hemorrhagic cystitis associated with high-dose Ifosfamide or Cyclophosphamide

amifostine

• cytoprotective agents

• MOA:

  • a prodrug that is converted by membrane-bound AP

  • the active metabolite has a free -SH group

• uses:

  • to reduce risk of radiation-induced xerostomia in patients with head and neck cancer

  • to reduce cumulative renal toxicity associated with Cisplatin in advanced ovarian cancer

platinum coordination complexes

• cisplatin

• carboplatin

• oxaliplatin

platinum compounds MOA

formation of intra-strand DNA adducts or crosslinking DNA strands or DNA to protein

cisplatin MOA

mechanisms of resistance towards Cisplatin

Cisplatin is taken up by specific transporters (copper transporter, organic cation transporters OCT)). Cisplatin is activated and forms DNA cross links (also called lesions).

1. reduction in expression of transporters responsible for uptake of Cisplatin

2. detoxification of reactive Cisplatin species by glutathione (GSH)

3. after formation of DNA crosslinks, enhanced nucleotide excision repair (NER) (a mechanism of DNA repair) causes removal of these lesions

4. alternatively, cancer cell can tolerate the formation of crosslinks and the DNA can be replicated as termed trans lesion synthesis (TLS)

   • the enzymes moving along the DNA strand jumps over the lesion area and continues its function

5. The formation of DNA crosslinks that are not adequately repaired triggers apoptosis. A mutation in p53 protein that results in loss of its function may reduce the probability that the cancer cell would undergo apoptosis and would result in clinical resistance

cisplatin nephrotoxicity

• cisplatin-induced nephrotoxicity is a well-documented adverse effect

• reduction of nephrotoxicity can be achieved with vigorous hydration and/or the use of amifostine

• cisplatin causes nephrotoxicty due to necrosis of proximal tubular epithelial cells

  • proximal tubular epithelial cells have elevated levels of expression of organic cation transporter resulting in enhanced Cisplatin uptake and intracellular accumulation

mechanisms of proximal tubular necrosis and apoptosis by Cisplatin

• cisplatin is uptaken by proximal tubular cells via copper and OCT transporters

• cisplatin is activated and forms DNA crosslinks

• the detoxifying capacity of proximal tubular cells is limited

• the p53 protein is activated resulting in activating intrinsic apoptosis

• cell damage occurs which reuslts in an irreversible loss in renal function

carboplatin

• shares similar clinical efficacy spectrum to that of Cisplatin

• Carboplatin is advantageous in the lack of renal toxicity evident with Cisplatin

  • Cisplatin is still being used b/c it’s superior in some cancers & carboplatin has ↑ risk of bone marrow suppression

antimetabolites

• a class of drugs that by virtue of its structural similarity to purine or pyrimidine bases or important cofactors (e.g. folic acid)

• inhibit the de-novo synthesis and DNA strand synthesis

  • de-novo synthesis is mandatory for cancer cells to meet the growth and cell division demands

• these drugs are classified as S-phase specific agents

  • the cells are most susceptible to the cytotoxic effect of these agents as they enter the S-phase

de-novo nucleotide synthesis

1. precursors stage

2. inosine monophosphate (IMP) is converted to GMP and AMP (purine bases)

3. uridine monophosphate (UMP) is converted to Cytosine diphosphate (CDP)

4. these are ribonucleotides (orange colored) that are converted to deoxyribonucleotides (blue) for incorporation into the DNA

5. deoxythymidine monophosphate (dTMP) is generated from deoxyuridine monophosphate (dUMP)

antifolates:

• agents

• methotrexate

• pralatrexate

• pemetrexed

antifolates MOA

• these drugs are structurally similar to folic acid (an important enzyme cofactor)

  • they compete with folic acid on binding to enzymes that require folic acid

• folic acid is essential in the de-novo synthesis of purine bases and in synthesis of dTMP

antifolates:

• main sites of action

1. inhibition of conversion of dUMP to dTMP

   • no pyrimidines

2. inhibition of generation of inosine monophosphate (IMP)

   • no GMP & AMP —> no purines

pemetrexed

more potent form of MTX bc it binds with higher affinity

pemetrexed MOA

• inhibition of dihydrofolate reductase (DHFR)

  • the enzyme responsible for regenerating tetrahydrofolate (THF) from dihydrofolate (DHF), allowing for the continued synthesis of purines and thymidylate

• inhibition of thymidylate synthase (TS)

  • the enzyme responsible for conversion of dUMP to dTMP for DNA synthesis

• inhibition of GARFT

  • the enzyme responsible for generation of AMP and GMP (purine nucleotides for DNA and RNA synthesis)

methotrexate:

• uptake into cells

• mediated by folic acid transporter

• once in cytosol, MTX is polyglutamated by folate polyglutamats synthase (FPGS)

• folate polyglutamate hydrolase (FPGH) can hydrolyze MTX-PG to MTX (which can diffuse back outside the cell)

• MTX is trapped in the cancer cell by being polyglutamated

methotrexate:

• targets

• DHFR inhibition

• thymidylate synthase

• enzymes responsible for IMP biosynthesis

MTX-polyglutamate

the inhibitor of target enzymes resulting in inhibition of dTMP, AMP and GMP biosynthesis

Leucovorin

• cytoprotectant

• folinic acid (reduced form of folic acid —> tetrahydrofolate)

• used as a chemoprotectant with antifolates to reduce the cytotoxic effect of antifolates on normal tissues

purine analogs:

• inhibitors of AMP and GMP biosynthesis

• mercaptopurine (6-MP)

  • inhibits AMP and GMP biosynthesis

• thioguanine (6-TG)

  • inhibits GMP biosynthesis

6-MP and 6-TG:

• toxicity

bone marrow suppression

6-MP and 6-TG:

• activation

hypoxanthine guanine phosphoribosyl transferase (HGRPT)

• 6-MP —> T-IMP —> inhibits the synthesis of AMP and GMP

• 6-TG —> 6-thioGMP —> inhibits the synthesis of GMP

6-MP and 6-TG:

• metabolism

6-MP:

• metabolized by xanthine oxidase (XO) —> 6-thiouric acid

6-TG:

• metabolized by thiopurine methyltransferase (TPMT) —> inactive metabolites

purine analogs:

• inhibitors of DNA strand sytnehsis

Cladribine and Fludarabine

Cladribine and Fludarabine MOA

• Cladribine and Fludarabine are converted to the triphospahte form and are incorporated into the nascent (developing) DNA strand

• once incorporated, DNA strand elongation is terminated and cell undergo apoptosis

pyrimidine analogs:

• inhibitors of dTMP biosynthesis

• 5-fluorouracil (5-FU) and capecitabine (prodrug)

• MOA: inhibition of dTMP biosyntehsis

• 5-FU is administered with Leucovorin (potentiates the cytotoxic effect of 5-FU)

capecitabine and 5-FU metabolism and activation

pyrimidine analogs:

• inhibitors of DNA strand synthesis

• Cytarabine (Ara-C) and Gemcitabine are structural analogs to cytidine

• Ara-C and gemcitabine are metabolized to triphosphate form which are incorporated in DNA

• this results in chain termination and apoptosis

hydroxyurea

inhibition of ribonucleotide reductase that catalyzes the conversion of ribonucleotides to deoxyribonucleotides

an independent effect of hydroxyurea (unrelated to its inhibition of de-novo DNA synthesis) is its use in management of Sickle Cell Disease

hydroxyurea in SCD

hydroxyurea enhances fetal hemoglobin production (Hb F)

• the Hb F- Hb S hybrids are less liekly to cause sickling of RBCs and results in veno-occlusion