Chemotherapy Flashcards
Multi-modal treatments
surgery, radiation, chemotherapy
Rationale for anti-neoplastic drugs
- kill all tumor cells
- suppress the growth of tumor but not normal cells
- increase host capacity to fight cancer
Ideal Ant-Neoplastic Drug
- non-toxic to normal cells
- kill all tumor cells
- broad spectrum of activity
- good distribution in body (adequate half-life)
- non-immunogenic
- low incidence of side effects
- low cost, oral dosing
Currently available chemotherapy
- Poor selective toxicity
- Most drugs only affect actively growing cells
- Have limited anti-tumor spectrum
- high incidence of side effects
- Cause secondary malignancy (after treatment of cancer time then develop second cancer)
Risk of Anti-Neoplastic drugs causing secondary malignancy
high risk: mechlorethamine, carmustine, topside
low risk: doxorubicin, cyclophosphamide,procarbazine, cisplatin
low risk: vincristine, vinblastine, methotrexate, cyarabine, 5-FC
unknown: paclitaxel, bleomycin
General ways to stop tumor growth
Cell death- cell killing compound
- direct kill (necrosis)
- trigger apoptosis
Stop Growth-cytostatic compound
- induce terminal differentiation
- interfere with growth signals
Mechlorethamine, Carmustine
Cell-cycle nonspecific
Alyklyating agent
Cyclophosphamide
Cell-cycle specific/ Phase non-specific
Alkylating Agent
Mechanism: introduce alkyl groups into DNA and cross links and cause strand break by forming aziridine ring (unstable)
Side effects: hematopoiesis suppression, GI effects through intestinal mcusoa, nausea and vomiting, alopecia
Alkylating agent
Mechlorethamine, Carmustine, Cyclophosphamide
Mechlorethamine
Alkylating Agent
MOA: bi functional alkylating agent that produces DNA cross-link
Combination therapy for Hodgkin’s and nOn-hodgkin’
Highly reactive so disappear in blood in seconds to minutes
Cyclophosphamide
Alkylating Agent
Prodrug activated by liver cytochrome P450s
Mechanism: The phosphoramide mustard acts as an alkylating agent
Bladder toxicity: sterile hemorrhagic cystitis (prevent with mesna)
Broad spectrum activity against wide variety of cancers (most widely used agent in this class)
Hodgkin’s and non-Hodgkin’s, multiple myeloma, neuroblastoma, leukemia
carcinoma of endometrium, breast, lung
Carmustine (BCNU)
Alkylating Agent
Cross the blood-brain barrier–> lipophilic
Uses: brain tumors, multiple myeloma, melanoma
Toxicity: similar to other alkylating agents
cycle-nonspecific
Methotrexate
Anti Metabolite Class (Folate Analog)
Mechanism: bind to dihydrogolate reductase (DHFR) and prevent formation of tetrahydrofolate (block FH2–>FH4) needed for thymidine synthesis
Side effects; intestinal epithelium damage, bone marrow suppression, renal tubular necrosis, displace other drugs from serum albumin, hepatotoxicity
Indications: acute lymphocytic leukemia, Choriocarcinoma (can cure)
Leucovorin Rescue
High doses methotrexate bind all dihydrofolate reductase (DHFR) and inhibits all activity
Follow by rescue with leucovorin
It is a folinic acid, a fully reduced floated that does not require reduction by DHFR
normal cells have increased capacity to bring in leucovorin relative to normal cells
Fluorouracil (5-FU)
Antimetabolite (Pyrimidine Analog)
Mechanism: pyrimidine analog that is activated in cells to FUTP which inhibits RNA synthesis and to Fdump which interferes with thymidylate synthase and ultimately DNA synthesis
S-Phase specific
Side effects; nausea, anorexia, diarrhea, myelosuppression
Broad spectrum uses: carcinoma of stomach, colon, pancreas, ovary, head and neck, breast, bladder and topical for basal cell carcinoma
Cytarabine (Ara-C)
Antimetabolite (pyrimidine analog)
Mechanism: pyrimidine (cytidine) analog that competes for phosphorylation of cytidine to dCTP and competes for incorporation into DNA and cause termination
S-Phase specific
Side effects: marked myelosuppression (dose-limiting) and neurotoxicity
Administer: 2 times daily for 5 days because increase probability for killing cells not in s phase and in acute nonlymphocytic leukemia S phase lasts about 18 hours
uses: acute leukemias (acute myelocytic leukemia)
Gemcitabine
Pyrimidine analog
similar to cyarabine but also inhibit ribonucleotide reductase
Treat: pancreatic cancer
Mercaptopurine
Antimetabolite (Purine Analog)
Mechanism: purine analog and converted in cells to ribonucleotide that inhibits RNA and DNA synthesis
S -Phase specific
Side effect: bone marrow depression, vomiting, nausea, anorexia, jaundice
Use: acute leukemia
Hydroxyurea
Antimetabolite
mechanism: inhibit ribonucleotide reductase to block conversion of ribonucleotide to dNTPs thereby preventing DNA synthesis
arrest in G1-S interface (useful in conjunction with radiation)
Use: granulocytic leukemia, head and neck cancer
side effects: hematopoietic depression, GI disturbance
Natural Products
Vinca alkaloids: Vincristine, Vinblastine Texans: Paclitaxel Epipodophyllotoxins: Etoposide Monoclonal Ab: Trastuzumab Antibiotics: Doxorubicin, Bleomycin
Vinca Alkaloids
Natural Product
Mechanism: binds to tubular, inhibiting proper formation of microtubule and mitotic spindle
Arrest cell in metaphase
Bind to singe tubulin microtubule rather than polymerized
Vinblastine
Side effects: strongly myelosuppressive (dose-limiting)
epithelial ulceration
Treat: Hodgkin’s and non-Hodgkin’s lymphomas, breast cancer
Vincristine
side effects: significantly less bone marrow toxicity
Alopecia, neuromuscular abnormalities (peripheral neuropathy)
Treat: acute lymphocytic leukemia, Hodgkin’s and Non-hodgkin’s lymphomas, Wilm’s Tumor, Neuroblastoma, rhabdomyosarcoma
Taxanes
Mechanism; enhance assembly and stability of microtubules by binding to Beta subunit of tubulin
block in G2 phase later (more sensitive to radiation so placlitaxel may have some use as radio sensitizer)
Bind to polymerized rather than individual microtubule
Paclitaxel
Uses: refractory ovarian cancer, breast cancer
Interfere with DNA repair, intensifying effect of DNA damage with cisplatin or cyclophosphamide
Side effects: dose-limiting leukopenia, peripheral neuropathy, myalgia, arthralgia
Doxorubicin
Natural Product (Antitumor antibiotic) Cycle-specific/phase non-specific (no Go cells)
Among most active of anti tumor agents
Uses : wide spectrum:most widely prescribed of the class but used specifically for Hodgkin’s and non-Hodgkin’s lymphoma, breast, ovary, small cell lung
Mechanism: intercalate in DNA, distort DNA helix, cause lipid peroxidation and free radical generation, and it bind to DNA and topoisomerase 2 (prevent DNA strand break)
Side effects: cardiomyopathy, bone marrow depression, alopecia, GI problems
Bleomycin
Mechanism: mixture of iron containing glycopeptides that bind to DNA and cause oxidative like damage to DNA which leads to DNA stand breaks (forms site specific ds DNA breaks)
phase specific for G2
Uses: germ cell tumors of testes and ovaries, head, neck, lung, lymphomas
Side effects: minimal myelosuppression, pulmonary toxicity (dose-related and cumulative and potentially fatal), skin vesiculation and hyper pigmentation
Etoposide
Mechanism: stabilizes DNA topoisomerase 2 complex which results in dsDNA breaks that cannot be repaired
Block in late G2 phase at M interface
Use: lymphoma, acute nonlymphocytic leukemia, small cell lung, testis, Kaposi’s sarcoma
Side effects: leukopenia (dose-limiting), nausea, vomiting, diarrhea, alopecia
Biological Response modifier
Natural Product
Intent: alter patient’s own biological response to a tumor or to treatment regimens
limitation: responseis variable
Filgrastin (G-CSF)
Goal: limit chemotherapy induced neutropenia
promotes progenitors of neutrophils and expands the absolute population of neutrophils (granulocyte production by marrow)
quick recovery with bone marrow suppression (neutropenia)
side effect: bone pain
Trastuzumab
Mechanism: monoclonal antibody that binds to HER2 receptor
Use: breast cancers that overexpress HER2
side effects: cardiomyopathy, hypersensitivity, infusion reactions
Cisplatin
Mechanism: platinum coordinated complex
hydrolysis yields activated species which causes DNA cross link
Cycle-specific/phase-nonspecific (no Go)
Wide anti tumor spectrum
Use: testicular cancer and ovarian, head, neck, bladder, small cell lung, colon, esophagus
Side effects: nephrotoxicity, ototoxicity, peripheral neuropathy, electrolyte disturbance, nausea and vomiting, myelosuppression
Procarbazine
Mechanism: activate in vivo to a methylating agent which causes a chromosomal damage
Use: Hodgkin’s lymphoma (G1 and S phase)
side effects : myelosuppression, nausea, vomiting, maybe secondary malignancy (DnA damage)
Prednisone
Hormone (Adrenocorticosteroid)
Mechanism: bind to steroid receptor which depress RNa synthesis of many growth related genes
also induce nucleases which modulate cell lysis
arrest cells in G1
Use: acute and chronic lymphocytic leukemia,
breast cancer, Hodgkin’s and non-Hodgkins’ disease
Palliative effects: anti-emetics, stimulate appetite, anti-inflammatory
Complication: immunosuppression but limited myelosuppression, weight gain, fluid retention, psychologic effect
Tamoxifen
MOA: Non steroidal anti estrogen that competitively blocks estrogen receptor activity in breast tissue
Cytostatic: held in Go/G1 phase and tumor regrows when tamoxifen removed
stops cell growth without killing the cells
Uses: advanced post menopausal breast cancer and pre-menopausal metastatic breast cancer
breast cancer prophylaxis for women at high risk
Activation : Activated by CYP2D6 (cancer recurrence if using CYP 2D6 inhibitor)
Side effects: nausea, hot flashes, fatigue, bone and musculoskeletal pain, increase rates of uterine/endometrial cancer
Raloxifene
Treat: uterine and endometrial cancer
Letrozole
mechanism: block conversion of androgen to estrogen by inhibing aromatase
Use: first line treatment of post-menopause advanced or metastatic breast cancer
side effect: hot flush, nausea, fatigue, bone and other musculoskeletal pain
Leuprolide
analog of GnRH
after 2-4 weeks it desensitizes GnRH signaling, decreasing LH/FSH and decreasing testosterone to castration levels
Use: advanced hormonally responsive prostate cancer
Side effects: hot flash and impotence
Flutamide
non steroidal androgen MOA: blocker of androgen receptor
Treat: metastatic prostate cancer
side effect: gynecomastia, diarrhea, hepatotoxicity
Vincristine and Prednisone and Doxorubicin
Acute Lymphocytic Leukemia
