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1193605
Cancer Chemotherapy
Description
step 1 Pharmacology Mind Map on Cancer Chemotherapy, created by Jeff Amos on 26/08/2014.
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unit 1
pharmacology
step 1
Mind Map by
Jeff Amos
, updated more than 1 year ago
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Jeff Amos
over 10 years ago
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Resource summary
Cancer Chemotherapy
Principles
indicated for cancers that are not amenable to surgery or radiation therapy
supplemental treatment to prevent metastasis following surgery or radiation
Log Kill Hypothesis
first order kinetics
kills constant fraction of cancer cells
Mechanisms
Interfere with cell proliferation or promote apoptosis
Inhibit DNA synthesis or alter DNA structure
Cell-Cycle Specific or Cell-Cycle Nonspecific
Combination Therapy
Principles of Drug Selection
individual anticancer activities
different mechanisms of action
different toxicities
Advantages
provide maximal killing with lower toxicity
Effective against heterogeneous cell populations
Reduces chance of resistance clones
Examples
ABVD
CHOP
MOPP
CMF
FEC
Limitations
Drug Resistance
Toxicities
Alkylating Agents
cell cycle non-specific
Mechanism of Action
produce strong electrophiles through the formation of carbonium or ethyleneiomonium ion intermediates
forms covalent linkage by alkylaation of nucleophilic moieties present in DNA
Binds to **N7 of guanine, N1 + N3 A, N3 C, O6 G
Resistance
decreased permeability
increased rates of metabolism
enhanced DNA repair
Increased production of glutathione
inactivates alkylating agents
Nitrogen Mustards
Mechlorethamine
Therapeutics
Hodgkin's Lymphoma (MOPP)
cutaneous T-cell Lymphoma
Toxicity
nausea and vomiting
myelosuppression
Cyclophosphamide and Ifosfamide
Therapeutics
C: ALL, CLL, non-Hodgkin's, breast, lung, ovarian
I: sarcoma and testicular
Toxicity
Nausea, vomiting, myelosuppression
Hemorrhagic Cystitis
acrolein in urine
treat with hydration and MESNA
Nitrosoureas
Carmustine and Lomustine
lipophilic
cross the blood-brain barrier
Toxicity
Nausea, vomiting, myelosuppression
Renal Toxicity
Pulmonary Fibrosis
Triazenes
Dacarbazine and Temozolomide
Therapeutic Uses
D: ABVD, Hodgkin's Disease, malignant Melanoma
T: malignant gliomas, combo with radiation therapy
Toxicity
Nausea, vomiting, myelosuppression
Flu-like symptoms (fever, fatigue)
Platinum Analogs
Cisplatin, Carboplatin, Oxaliplatin
No carbonium ion intermediates
covalently bind to nucleophilic sites
Therapeutics
Cis: testicular, ovarian, cervical, bladder, head and neck, lung, combos
Carb: ovarian
Ox: gastric and colorectal (with 5-FU)
Toxicity
Cis: renal toxicity, ototoxicity, peripheral neuropathy
Carb: myelosuppression
Ox: peripheral sensory neuropathy (cold induced acute peripheral neuropathy), neutropenia
Antimetabolities
Mechanism
structural analogs of endogenous metabolites
replace and compete with nucleotides
Cell-Cycle specific Drugs
Folate Analogs
Methotrexate
folic acid anatagonist
inhibits dihydrofolate reductase
Required for thymidine and purine biosynthesis
Therapeutics
ALL
Burkitt's Lymphoma
Breast, ovary, head and neck, bladder
Cannot penetrate the CNS
Osteosarcoma
Toxicity
Myelosuppression and spontaneous hemorrhage
oral ulceration and stomatitis
Renal toxicity through crystallization
Hepatotoxicity
Defective oogenesis or spermatogenesis
Mechanism of resistance
reduced drug uptake
Decreased affinity of DHFR
Increased production of DHFR
Pemetrexed
Targets DHFR and thymidylate synthase
Used for colon, pancreatic, mesothelioma and non-small cell lung
Pyrimidine Analogs
5-Fluorouracil
pro-drug conversion to 5-FdUMP and 5-FdUTP
inhibits thymidylate synthetase (blocks synthesis of thymidine)
incorporates into RNA, interferes with function
Therapeutics
breast, colorectal, gastric, head and neck, cervical and pancreatic cancer
Topical to treat basal cell carcinomas
Capecitabine
metastatic breast and colorectal cancer
5'-dFdU
Toxicity
Gastric toxicity (why it is IV)
anorexia and nausea, myelosuppression
Hand-Foot Syndrome
Cardiac Toxicity
Cytarabine
analog of 2'-deoxycytidine
converted to Ara-CMP, then Ara-CTP
Competes with dCTP
Therapeutics
AML
ALL and CLL
Toxicity
myelosuppression and GI tract toxicity
S-phase specific
Gemcitabine
analog of deoxycytidine
altered to dFdCMP then dFdCDP or dFdCTP
inhibits DNA sythesis
dFdCDP inhibits ribonucleotide reductase
dFdCTP causes DNA synthesis termination
cell cycle nonspecific
Therapeutics
pancreatic cancer
non-small cell lung cancer, ovarian, bladder, esophageal, head and neck
Toxicities
Myelosuppression
Flu like symptoms
Purine Analogs
6-Mercaptopurine
reduces purine levels, inhibiting DNA and RNA synthesis
metabolized by HGPRT to TIMP
blocks first step in purine synthesis
blocks AMP and xanthinylic acid from inosinic acid
converted to thio-guanine ribonucleotides
inhibit DNA and RNA synthesis
Therapeutics
ALL
Toxicities
bone marrow suppression
hepatotoxicity from prolonged use
Allopurinol use
blocks xanthine oxidase
causes elevated levels of mercaptopurine
Mechanism of Resistance
reduced conversion of 6-MP to active nucleotide (decreased expression of HGRPT)
decreased drug transport
DNA Intercalating Agents
AKA anti-tumor antibiotics
from Streptomyces
DNA through intercalation
block DNA and RNA synthesis
causes DNA strand breaks
Dactinomycin
Mechanism
intercalates between G-C forming dactinomycin-DNA complex
interferes with DNA-dependent RNA polymerase
single strand breaks
Therapeutics
pediatric tumors: Wilm's tumor, rhabdomyosarcoma, Ewing's sarcoma
Toxcitiy
Severe hematopoietic suppression with pancytopenia
GI symptoms
Anthracyclins
reduce intermediates that donate electrons, forming superoxide
forms destructive hydroxyl radical that cleaves DNA
Toxicity
irreversible dose-limiting cardiotoxicity (cardiomyopathy)
Myelosuppression and GI symptoms
Therapeutics
Daunorubicin and Idarubicin
AML
Doxorubicin
sarcomas, breast and lung, malignant lymphomas
Epirubicin
metastatic breast cancer and gastric cancer
Bleomycin
Mechanism
contains 2 copper chelating peptides
forms free radicals
causes single and double strand breaks
Acts during G2
Therapeutics
testicular tumors (with vinblastine or etoposide)
squamous cell carcinomas and lymphomas
Toxicity
minimally myelo- and immunosuppressive
used in combination with other drugs
Pulmonary Toxicity
Cutaneous toxicity
Hyperthermia, headache, nausea, vomiting
Microtubule Inhibitors
block assembly and disassembly of MTs
functions in metaphase
Vinca Alkaloids
Vinblastine and Vincrstine
Mechanism
bind to tubulin and block ability to polymerize
Therapeutics
Vinblastine
with Bleomycin and cisplatin for metastatic testicular cancers
Part of ABVD (adriamycin [doxorubicin], bleomycin, vinblastine and dacarbazine)
Hodgkin's Lymphoma
Vincristine
with glucocorticoids for childhood ALL
Hodgkin's and non-Hodgkin's Lymphoma (MOPP)
Toxicity
Vinblastine
myelosuppresion, GI
Vincristine
Dose-limiting neurotoxicity (peripheral neuropathy)
low toxicity in the bone
Taxanes
Mechanism
promote polymerization and stabilize MTs
prevent breakdown
Therapeutics
Paclitaxel and Docetaxel
metastatic breast, ovarian, lung, head and neck.
Docetaxel
hormone-refractory prostate cancer
Toxicity
Neutropenia, peripheral neuropathy, hypersensitivity
Topoisomerase Inhibitors
Topoisomerase mediate DNA strand breakage and resealing
Topo I breaks and seals single stranded
Topo II breaks and seals double stranded DNA
Epipodophyllotoxins
Etoposide and Teniposide
Mechanism
inhibit Topo II, causing DNA damage
semisynthetics of podophyllotoxin
Therapeutics
Etoposide
testicular carcinoma, lung cancer, non-Hodgkin's Lymphoma
Teniposide
ALL
Toxicity
dose-limiting myelosuppression (neutropenia)
Oral Mucositis
Camptothecin Analogs
Mechanism
inhibit Topo I
Therapeutics
Irinotecan
advanced colon cancer
lung, ovarian, cervical, brain tumors
Topotecan
ovarian and small cell lung cancer
Toxicity
severe neutropenia and severe diarrhea
Hormones and Antagoists
used for hormone dependent neoplasms
breast and prostate cancer
glucocorticoids
treat lymphocytic leukemias and lymphomas
Mechanism
inhibit mitosis in lymphocytes
no immunosuppression and well tolerated
Therapeutics
Prednisone
ALL
part of MOPP and CHOP for Hodgkin's and non-Hodgkin's, multiple myeloma and CLL
Dexamethasone
Dexamethasone
in conjuction with radiation therapy
reduces edema to brain and spinal cord tumors
Estrogen antagonists
breast cancer
Androgen antagonists
prostate cancer
Selective Estrogen-Receptor Modulators
Tamoxifen
competes with estradiol for ER binding
Therapeutics
ER-positive metastatic breast cancer or adjuvant therapy following primary breast tumor excision
prevention of breast cancer in high-risk patients
Toxicity
hot flushes, hair loss, nausea, vomiting
increase risk of endometrial cancer and thromboembolic events
Selective Estrogen-Receptor Downregulators
Fulvestrant
Mechanism
binds to ER, preventing dimerization
Reduces number of ER molecules
Therapeutics
postmenopausal women with ER-positive metastatic breast cancer
Aromatase Inhibitors
inhibit aromatase enzyme, causing estrogen decrease
Aminoglutethamide
weak inhibitor
significant toxicity
Anastrozole
potent and selective inhibitor
ER-positive breast cancer in postmenopausal women
Prostate Cancer Treatments
Leuprolide (Lupron) and Goserelin (Zoladex)
GnRH analogs
inhibit release of LH and FSH
Decreased Testosterone Production
Complete androgen ablation therapy involves combination of GnRH analogs and AR blockers
Flutamide and Bicalutamide
nonsteroidal androgen-receptor blockers
compete for androgen receptor and prevent its translocation to nucleus
Miscellaneous Agents
Hydroxyurea
inhibits ribonucleside diphosphate reductase
converts ribonucleosides to deoxyribonucleosides
Therapeutics
myeloproliferative neoplasms, polycythemia vera and essential thrombocythemia
Retinoids
treats acute promyelocytic leukemia
induces differentiation in leukemic promyelocytes
Arsenic Trioxide
treats relapsed APL
Thalidomide
treats multiple myeloma and myelodysplastic syndromes
Interferons
IF alpha for hairy cell leukemia, CML, AIDS relate Kaposi's sarcoma
Tyrosine Kinase Inhibitors
Imatinib
inhibits Abl kinase, PDGFR and c-kit
treats CML and GI tumor
Gefitinib and Erlotinib
inhibit EGFR tyrosine kinase
treats non-small cell lung cancer
Monoclonal Antibodies
Rituximab
targets CD20 B-cell antigen
Treats non-Hodgkin's Lymphoma
Trastuzumab
antibody against HER2/neu
treats HER2/neu-overexpressing breast cancer
Cetuximab
antibody against EGFR1 (ErbB1
approved for EGFR-positive colorectal cancer
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