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Cancer Chemotherapeutic Agents - Coggle Diagram

- - - - It is structurally related to folic acid which is essential for cell replication
      - A folic acid antagonist
    - - This decreases production of nucleotides (adenine, guanine, thymidine) & amino acids (methionine & serine)
      - Decrement in DNA, RNA & protein synthesis -> cell death
      - MTX inhibits dihydrofolate reductase (DHFR), an enzyme that converts folic acid to dihydrofolic acid (FH2), and then to its active coenzyme form, tetrahydrofolic acid (FH4)
    - - Metabolized to polyglutamate derivatives (active metabolite which also inhibit DHFR)
      - Metabolized to 7-hydroxymethotrexate (less active, less water-soluble & may lead to crystalluria) -> thus, need to keep urine to be alkaline & patient well-hydrated to avoid renal toxicity
      - Given IM, IV & intrathecal (cannot pass BBB easily)
      - Inhibition of DHFR by MTX can only be reversed by: a 1000-fold excess of dihydrofolate (FH2) & leucovorin (folinic acid) which bypasses the blocked enzyme
    - - Renal damage (uncommon): urine alkalization & hydration help to prevent this problem
      - Hepatic function: long term use may lead to cirrhosis
      - Stomatitis, myelosuppression, erythema, rash & urticaria (common)
      - Pulmonary toxicity (rare)
      - Nausea, vomiting diarrhea & alopecia (common)
      - Children on MTX may develop cough, dyspnea, fever & cyanosis
      - Neurologic toxicities: associated with intrathecal administration, may include sub-acute meningeal irritation, stiff neck, headache & fever. Rarely, seizures, encephalopathy or paraplegia occur
      - Long-lasting learning disabilities in children
    - - MTX is teratogenic in experimental animals & is an abortifacient, it should be avoided in pregnancy (MTX is used with prostaglandin analog, misoprostrol to induce abortion)
  - - - Myelosuppression (major)
      - Anorexia, nausea, vomiting & diarrhea
      - Hepatotoxicity: Jaundice has been reported in about 1/3 of adult patients
    - - 6-MP undergoes few conversions & then incorporated into DNA -> result in synthesis of non-functional DNA -> DNA damage-induced cell death
      - One of the anti-purines that can be administered orally
  - - - It penetrates well into all tissues including CNS
      - Converted to fluoro-B-alanine, which is removed in urine & to CO2 which is exhaled
      - Given IV, topical (skin cancer)
    - - Leucovorin is administered with 5-FU for thymidylate synthetase inhibition
      - Addition of leucovorin increases effectiveness of 5-FU to form a ternary complex & produce an anti-pyrimidine effect
      - Basically, it interferes with conversion of deoxy-uridylic acid to thymidylic acid, thus depriving cell of thymidine (an essential precursor for DNA synthesis)
      - Standard regimen for advanced colorectal cancer today is irinotecan plus 5-FU + leucovorin
      - One of anti-pyrimidines
    - - Nausea, vomiting, diarrhea, alopecia, severe ulceration of oral & GI mucosa, myelosuppression & anorexia (common)
      - "Hand-foot syndrome" is seen after extended infusions
- - - - It intercalates into minor groove of double helix DNA forming a stable dactinomycin-DNA complex -> interferes primarily RNA synthesis
      - At high doses, it causes single-strand breaks possibly due to action on topoisomerase II or by generation of free radicals
    - - Myelosuppression, immunosuppression, nausea, vomiting, diarrhea, stomatitis & alopecia
    - - Administered IV & distributed to many tissues but does not enter CSF
      - Also known as actinomycin D
  - - - Doxorubicin interacts with molecular O2, producing superoxide ions & hydrogen peroxide radicals which cause single-strand breaks in DNA
    - - Administered IV (because they are inactivated in GIT)
      - Extravasation is a serious problem that can lead to tissue necrosis
      - Because of the dark red color of anthracycline drugs, veins may become visible surrounding infusion site & the drugs also impart a red color to urine
    - - Doxorubicin - hydroxylated analog of daunorubicin
      - They are anthracycline antibiotics
    - - Stomatitis
      - GI tract disturbances
      - Myelosuppression (transient)
      - Increased skin pigmentation
      - Cardiotoxicity - dose-dependent & irreversible; result from free radicals & lipid peroxidation; a new liposomal-encapsulated doxorubicin is less-cardiotoxic than usual formulation
      - Alopecia (usually severe)
  - - - The liberated electrons react with O2 to form superoxide or hydroxyl radicals
      - These radicals then attack the phosphodiester bonds of DNA, resulting in strand breakage & chromosomal aberrations
      - A DNA-bleomycin-Fe2+ complex appears to undergo oxidation to bleomycin-Fe3+
    - - Administered by subcutaneous, IM, IV & intra-cavitary
      - Bleomycin-inactivating enzyme (hydrolase) is high in a number of tissues (liver & spleen) but is low in lung & is absent in skin (accounting for drug's toxicity in those tissues)
    - - Bleomycin cause DNA scission by an oxidative process
    - - Hypertrophic skin changes & hyperpigmentation of hands are prevalent
      - Fever & chills (common)
      - Serious anaphylaxis (rare)
      - Alopecia (common)
      - Pulmonary toxicity: most serious adverse effect, progressing from rales, cough & infiltrate to potentially fatal pulmonary fibrosis, often referred as "bleomycin lung". Why? Low hydrolase (bleomycin-inactivating enzyme) in lung
      - Myelosuppression (rare)
- - - - It alkylates guanine residue in one or both strands of DNA molecule leading to DNA strand breakage
      - Only administered IV
    - - Severe nausea & vomiting
      - Myelosuppression (severe): limits extensive use
      - Viral infections (eg: herpes zoster) because of immunosuppression
      - Extravasation (serious)
    - - Developed as vesicant (blistering agents) during WW1
      - Also known as nitrogen mustard
  - - - Both are first bio-transformed to hydroxylated intermediates primarily in liver by CYP450 system
      - The hydroxylated intermediates then undergo breakdown to form active phosphoramide mustard & the toxic acrolein
      - Reaction of phosphoramide mustard with DNA is considered to be the cytotoxic step (alkylation)
      - Administered IV, oral
    - - They are pro-drugs- cytotoxic only after generation of their alkylating species
      - Very closely-related mustard agents -> share most of similar primary mechanisms & toxicities but unique because they can be taken orally
    - - Myelosuppression (eg: hemorrhagic cystitis) which can lead to fibrosis of bladder
      - ::::::::Hemorrhagic cystitis has been attributed to acrolein in urine
      - Alopecia, nausea, vomiting & diarrhea (prominent)
      - ::::::::::Adequate hydration as well as IV injection of MESNA (sodium 2-mercaptoethane sulfonate) which neutralizes the toxic acrolein, will minimize this problem
      - Effects on germ cells: Amenorrhea, testicular atrophy, aspermia & sterility
      - Veno-occlusive disease of liver: 25% of patients
      - Secondary malignancies: may appear years after therapy
  - - - They alkylate DNA in resting & actively dividing cells -> inhibits replication & eventually RNA & protein synthesis
      - Carmustine is administered IV, while lomustine is given orally
    - - Aplastic marrow (prolonged use)
      - Renal toxicity
      - Pulmonary fibrosis
      - Diabetogenic (streptozotocin)
    - - Carmustine, lomustine & streptozotocin