• dactinomycin
• doxorubicin/adriamycin
• bleomycin

1. inserts self between base pairs
2. this "intercalating" causes a change in confirmation
   1. retention and accumulation of this correlates with antitumor effectiveness
3. interfere with enzymes that read DNA
   • esp. DNA dependent RNA polymerase

toxicity- radiation recall (potentiation of previous radiation toxicity)

1. intercalates into DNA
2. this inhibits topoisomerase II
3. inhibits DNA synthesis
4. inhibits separation of duplex DNA strands

Also interfere with ion transport and in the presence of iron, it forms superoxide radicals that cause lipid peroxidation and mitochondrial damage

lower topoisomerase levels

• cardiotoxicity (dose limiting feature)
  • mechanism- as metabolite doxorubinol and free radical formation inhibiting HER2 gene required for normal heart function
  • dose related CHF resistant to tx many yrs later
  • acute affect on rhythm (unrelated to dose)
• radiation recall

1. mix of several drugs that bind to, intercalate, and fragment DNA
2. causes cytotoxicity

• very lil toxicity to bone marrow, so good for combo with other anti-tumor drugs
• major toxicity
  • lung- pneumonitis, pulmonary fibrosis
  • skin- hyperpigmentation
  • these tissues, along with tumor cells, lack the enzyme that inactivates bleomycin: bleomycin hydrolase

1. dissolution of lymphocytes
2. regression of LN

• breast CA
• prostate CA
• endometrial CA

• androgen antagonist- flutamide
• GnRH agonist: leuprolide or goserelin
• 5 alpha reductase inh: finasteride

• ER alpha + receptors
• PR+ receptors

In the absence of these receptors, successful endocrine tx is limited

• both antagonist and agonist activity
  1. demethylation and hydroxylation via CYP2D6 alters the drug to its active metabolite endoxifen
     • CI: SSRI's (they inh. CYP2D6)
  2. estrogen blocking effects on breast tumor cell, preventing growth
  3. estrogen like effects on bone, preventing osteoporosis

• increase in endometrial cancer (estrogen like effects on uterus)
• increase in thromboembolism and stroke in women over 50
• hot flashes, vaginal bleeding

• mutation of estrogen R protein
• alteration in shape of receptor
• switch to estrogen unrelated stimulation of breast tumor tissue

• aromatase inhibitor
  • block formation of estrogens from androstenedione and testosterone
• indication- ER positive post menopausal metastatic breast cancer patients
  • good alternate to tamoxifen in women whom it is CI as first line tx
  • NOT in premenopausal women due to high ovarian estrogen levels
• toxicity- encourage bone resportion, with possible increase risk of bone fracture and bone pain

• mechanism- monoclonal Ab against HER-2 oncogene (abundant on tumor cells)
  • decrease attachment of GF's
  • leads to slowing of abnormal growth
  • CI: tumors w/o HER2 overexpression
• toxicity- cardiac dysfunction
  • higher risk with doxorubicin

vincristine

vinblastine

vinca alkaloids: mechanism of action

1. binds to tubulin (M phase specific)
2. inhibit tubulin polymerization into MT's
3. decreaed microtubules
4. decreased chromatid separation and cell division
5. block metaphase

• vinecristine- neurotoxicity
  • leukemia, some solid tumors
• vinblastine- bone marrow toxicity
  • solid tumors

• mechanism
  1. promote stable MT's
  2. interfere with normal disassebly and cell division
  3. produces abberant mitosis, chromosomal breakage, mitosis arrest
• indication- unresponsive cancers
• toxicity
  • neutropenia
  • neuropathy
  • cardiac ischemia
  • hypersensitivity

• mechanism of action (biochemical difference)
  1. this enzyme deaminate Asn in serum
  2. this will decrease serum Asn
  3. bacteria need Asn, so they will die
• resistance mechanism- make own Asn
• toxicity- mainly in adult pts

• mechanism
  • inhibits topisomerase II
  • decrease DNA synthesis and degraded DNA
• resistance- low levels of topoisomerase or mutated topoisomerase
• toxicity- myelosuppression, carcinogenic

• mechanism
  1. inhibit ribonucleoside diphosphate reductase
  2. inhibit DNA synthesis
• indication: CML, sickle cell anemia
• toxicity: myelosuppression

• mechanism of action- inhibit BCR-ABL TK binding site for ATP
• indication- CML

• reduce marrow toxicity so you can use higher doses of antitumor drugs
• anti-emetics to reduce GI toxicity (NV)
• increase dose intensity of chemotx agents enhance success rates
• anti-tumor drugs in combination

• bone marrow replacement
• G-CSF
• EPO

• ondensteron combined with corticosteroids (dexamethasone)
  • mechanism of ondensterone- 5 HT₃ antagonist
• aprepitant
  • mechansim- neurokinin NK1 receptor antagonist (prolonged protection)

• possible synergism between drugs greatly enhances antitumor action
• drugs with different mechanisms of anti tumor action may produce greater anti-tumor efficacy
• drugs with different toxicities may permit higher doses of such drugs, thereby producing more antitumor selectivity
• combinations may reduce likelihood of emerging resistance to drugs

• drugs with limited myelosuppression
  • bleomycin
  • vincristine
  • methotrexate with leucovorin
  • cis-platin
• combine these drugs with other drugs which are toxic to bone marrow
  • ex: MOPP (Hodgkin's lymphoma), ABVD (Hodgkin's lymphoma), CMA, CHOP