Mechlorethamine
Cell-cycle nonspecific.
Nitrogen Mustard, Alkylating Agent: Bifunctional alkylation; produces DNA crosslinks. Highly reactive and not measurable in blood after seconds
Tx
- Rarely used
- Hodgkin’s Lymphoma
- Non-Hodgkin’s Lymphoma
IV only, will not enter CNS.
Cyclophosphamide
Cell-cycle specific, phase non-specific
Nitrogen Mustard, Alkylating Agent
Tx
1. Broad spectrum
Oral or Parenteral, will not enter CNS
SE
1. Bladder toxicity (Sterile Hemorrhagic Cystitis), caused by other product made during activation (Acrolein. Treat acrolein toxicity with mesna.)
Prodrug, activated by liver cytochrome P450s
Carmustine
Cell-cycle nonspecific
Nitrosureas, Alkylating Agent
Tx
- Brain Tumors
- Multiple Myeloma
- Melanoma
This class can penetrate CNS
Methotrexate MTX
Cell-cycle S-Phase specific
Antimetabolite
Folate Analog: Binds DHF Reductase, preventing THF production. This blocks pyrimidine and purine synthesis.
Tx
- Acute lymphocytic leukemia (ALL)
- Choriocarcinoma
SE
- Intestinal epithelium damage (diarrhea, bleeding)
- Bone marrow suppression
- Renal tubular necrosis (limited by maintaining alkaline urine)
- High serum album binding, can thus increase plasma plasma concentration of other album-binding drugs by competing for binding
- Hepatotoxic
- CNS abnormality
Methotrexate is given in high doses. Normal cells are rescued with leucovorin, which is a fully reduce folate (folinic acid) that does not need DHFR conversion. Normal cells are better suited to uptake leucovorin than tumor cells, leading to preferential killing.
Fluorouracil (5-FU)
Cell-cycle S-Phase specific
Antimetabolite
Pyrimidine Analog: Activated in cells to F-UTP, which limits RNA synthesis, and to FdUMP, which interferes with thmidylate synthase and ultimately DNA synthesis
Tx (very broad, but especially colon and breast)
- Stomach, colon, pancreas, ovary, head and neck, breast and bladder.
- Basal cell carcinoma
SE
- Nausea, anorexia, diarrhea
- Myelosuppression
Cytarabine
Cell-cycle S-Phase specific
Antimetabolite
Pyrimidine (Cytidine) Analog: Competes for phosphorylation of Cytidine. Causes chain termination as it competes for DNA incorporation
Tx
1. Acute Leukemias (especially acute myelocytic leukemia)
SE
- Myelosuppression (dose-limiting)
- Neurotoxicity
Mercaptopurine
Cell-cycle S-Phase specific
Antimetabolite
Purine Analog: Converted in cells to ribonucleotide that inhibits RNA and DNA synthesis
Tx
1. Acute Leukemias
SE
- Bone Marrow Suppression
- Vomiting, Nausea, Anorexia
- Jaundice
***Careful with people with TPMT deficiencies (severe bone marrow suppression, aplastic anemia)
Hydroxyurea
Cell-cycle G1-S interface specific
Antimetabolite
Substituted urea: Blocks ribonucleotide reductase, preventing dNTP formation and DNA synthesis
Tx
1. Granulocytic Leukemia
SE
1. Hematopoietic Depression, GI Disturbances
Useful in conjunction with radiation (cells need dNTPs to repair radiation-induced DNA damage)
Vinblastine
Cell-cycle M-phase specific
Vinca Alkaloid
Bind tubulin, block microtubule/mitotic spindle formation
Tx
- Lymphomas
- Breast Cancer
SE
- Strong myelosuppressive (dose-limited)
- Epithelial ulcerations
Vincristine
Cell-cycle M-phase specific
Vinca Alkaloid
Bind tubulin, block microtubule/mitotic spindle formation
Tx
- Acute lymphocytic leukemia (ALL)
- Lymphomas
- Wilm’ Tumor
- Neuroblastoma
SE
- Alopecia
- Neuromuscular abnormalities
- Peripheral Neuropathy
Paclitaxel
Cell-cycle late G2 (G2/M interface) specific
Taxane
Enhances stability of microtubules and their assembly by binding the beta-subunit.
Tx
- Refractory ovarian cancer
- Breast cancer
SE
- Dose-limiting leukopenia
- Peripheral neuropathy
- Myalgia/arthralgia
Also harms DNA repair, intensifies DNA-damaging agents
Doxorubicin
Cell-cycle specific, phase nonspecific
Has anti-angiogenic properties. Intercalates DNA, distorts the helix. Causes lipid peroxidation and free radical generation. Binds to DNA + Topoisomerase II
Tx
- Wide spectrum
- Lymphomas
- Breast
- Ovary
- Small cell lung
SE
- Cardiomyopathy
- Bone marrow suppression
- Alopecia
- GI problems
Bleomycin
Cell-cycle G2/M phase specific
Mixture of iron-containing glycopeptides that binds DNA. Causes oxidative-like damage to DNA, leading to strand breakage
Tx
- Germ cell tumors of testes and ovaries
- Head and neck cancer
- Lung cancer
- Lymphomas
SE
- Minimal myelosuppression
- Pulmonary toxicity (e.g. pneumonitis, fibrosis), dose related and cumulative (potentially fatal)
- Skin vesiculation, hyper pigmentation
Lung and skin have lowest levels of bleomycin hydrolase needed to process drug
Etoposide
Cell-cycle G2/M interface specific (late G2)
Irrversibly stabilizes DNA-topoisomerase II complexes, leading to irrepairable dsDNA breaks
Tx
- Lymphomas
- Acute Leukemia
- Small Cell Lung
- Tetis
SE
- Leukopenia
- Nausea, Vomiting, Diarrhea
- Alopecia
Filgrastim (G-CSF)
Biological Response Modifier
Granulocyte colony stimulating factor: Limits chemotherapy-induced neutropenia by promoting progenitors of neutrophils and expands their population. Quicker bone marrow suppression recovery. Less infection risks and allows maintenance doses to be tolerated without a gap. (all ideal)
SE
1. Bone pain
Trastuzumab
Monocolonal antibody that binds to HER2 receptor (human epidermal growth factor receptor)
25-30% of breast cancers overexpress HER2, and these cancers are less responsive to anti-estrogen strategies except for doxorubicin and paclitaxel
Tx
1. Breast cancer
SE
- Cardiomyopathy
- Hypersensitivity
- Infusion reactions (fever, chills)
Cisplatin
Cell-cycle specific, phase non-specific
Platinum coordination complex
Activated species causes DNA cross links
Tx
- Testicular cancer
- Ovarian cancer
- Head and neck cancer
- Small cell lung cancer
- Colon cancer
- Esophagus cancer
SE
- Nephrotoxicity
- Ototoxicity
- Peripheral neuropathy
- Electrolyte disturbances
- Nausea and vomiting in ALL patients (100%!)
- Myelosuppression
Procarbazine
Atypical Alkylating Agent: Activated in vivo by liver to a methylating agent causing chromosomal damage. NO CROSS RESISTANCE with other alkylating agents!
G1/S is best
Tx
1. Hodgkin’s lymphoma
SE
- Myelosuppression
- Nausea and vomiting
Prednisone
G1 arrest
Steroid: Depresses expression of many growth-related genes, induces nucleases that modulate cell lysis
Tx
- Lymphoma
- Leukemia
- Breast Cancer
SE
1. Immunosuppression
Palliative effects:
- Anti-emetic
- Appetite stimulant
- Anti-inflammatory
Tamoxifen
Cytostatic; holds sells in G0/G1
Nonsteroidal antiestrogen: Competitively blocks estrogen receptors in breast tissue. Tumor regrows when the agent is withdrawn. Stops cell growth, but does not necessarily kill them. Activated by CYP2D6 (be cognizant of drug interaction and ultrafast metabolizers!)
Tx
- Advaned post-menopausal breast cancer
- Pre-menopausal metastatic breast cancer
- Breast cancer prophylaxis for women at high risk (reduces chance by 45%)
SE
- Nausea
- Hot flashes
- Fatigue
- Bone and other musculoskeletal pain
Letrozole
Aromatase Inhibitor: Blocks conversion of androgens to estrogens.
Tx
1. First line treatment for post-menopausal locally advanced or metastatic breast cancer
SE
- Hot flushes
- Nausea
- Fatigue
- Bone and other musculoskeletal pain
Leuprolide
Antiandrogen
GnRH analog: Stimulates LH and FSH, causing testostorone surge and disease flare initially. After 2-3 weeks, GnRH signaling is desensitized, LH/FSH fall off and testosterone is down to castration-type levels
Tx
1. Advanced, hormonally responsive prostate cancer
SE
- Hot flashes
- Impotence
Flutamide
Nonsteroidal antiandrogen: Blocks androgen receptors
Tx
1. Metastatic prostate cancer, can be used in combination with GnRH agonist
SE
- Gynecomastia
- Diarrhea
- Hepatoxicity
