Cancer Chemotherapy

Jeff Amos
Mind Map by , created about 5 years ago

step 1 Pharmacology Mind Map on Cancer Chemotherapy, created by Jeff Amos on 08/26/2014.

Jeff Amos
Created by Jeff Amos about 5 years ago
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Cancer Chemotherapy
1 Principles
1.1 indicated for cancers that are not amenable to surgery or radiation therapy
1.2 supplemental treatment to prevent metastasis following surgery or radiation
1.3 Log Kill Hypothesis
1.3.1 first order kinetics
1.3.2 kills constant fraction of cancer cells
1.4 Mechanisms
1.4.1 Interfere with cell proliferation or promote apoptosis
1.4.2 Inhibit DNA synthesis or alter DNA structure
1.4.3 Cell-Cycle Specific or Cell-Cycle Nonspecific
1.5 Combination Therapy
1.5.1 Principles of Drug Selection individual anticancer activities different mechanisms of action different toxicities
1.5.2 Advantages provide maximal killing with lower toxicity Effective against heterogeneous cell populations Reduces chance of resistance clones
1.6 Limitations
1.6.1 Drug Resistance
1.6.2 Toxicities
2 Alkylating Agents
2.1 cell cycle non-specific
2.2 Mechanism of Action
2.2.1 produce strong electrophiles through the formation of carbonium or ethyleneiomonium ion intermediates forms covalent linkage by alkylaation of nucleophilic moieties present in DNA
2.2.2 Binds to **N7 of guanine, N1 + N3 A, N3 C, O6 G
2.3 Resistance
2.3.1 decreased permeability
2.3.2 increased rates of metabolism
2.3.3 enhanced DNA repair
2.3.4 Increased production of glutathione inactivates alkylating agents
2.4 Nitrogen Mustards
2.4.1 Mechlorethamine Therapeutics Hodgkin's Lymphoma (MOPP) cutaneous T-cell Lymphoma Toxicity nausea and vomiting myelosuppression
2.4.2 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
2.5 Nitrosoureas
2.5.1 Carmustine and Lomustine lipophilic cross the blood-brain barrier Toxicity Nausea, vomiting, myelosuppression Renal Toxicity Pulmonary Fibrosis
2.6 Triazenes
2.6.1 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)
2.7 Platinum Analogs
2.7.1 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
3 Antimetabolities
3.1 Mechanism
3.1.1 structural analogs of endogenous metabolites
3.1.2 replace and compete with nucleotides
3.2 Cell-Cycle specific Drugs
3.3 Folate Analogs
3.3.1 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
3.3.2 Pemetrexed Targets DHFR and thymidylate synthase Used for colon, pancreatic, mesothelioma and non-small cell lung
3.4 Pyrimidine Analogs
3.4.1 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
3.4.2 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
3.4.3 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
3.5 Purine Analogs
3.5.1 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
4 DNA Intercalating Agents
4.1 AKA anti-tumor antibiotics
4.1.1 from Streptomyces
4.2 DNA through intercalation
4.2.1 block DNA and RNA synthesis
4.2.2 causes DNA strand breaks
4.3 Dactinomycin
4.3.1 Mechanism intercalates between G-C forming dactinomycin-DNA complex interferes with DNA-dependent RNA polymerase single strand breaks
4.3.2 Therapeutics pediatric tumors: Wilm's tumor, rhabdomyosarcoma, Ewing's sarcoma
4.3.3 Toxcitiy Severe hematopoietic suppression with pancytopenia GI symptoms
4.4 Anthracyclins
4.4.1 reduce intermediates that donate electrons, forming superoxide forms destructive hydroxyl radical that cleaves DNA
4.4.2 Toxicity irreversible dose-limiting cardiotoxicity (cardiomyopathy) Myelosuppression and GI symptoms
4.4.3 Therapeutics Daunorubicin and Idarubicin AML Doxorubicin sarcomas, breast and lung, malignant lymphomas Epirubicin metastatic breast cancer and gastric cancer
4.5 Bleomycin
4.5.1 Mechanism contains 2 copper chelating peptides forms free radicals causes single and double strand breaks Acts during G2
4.5.2 Therapeutics testicular tumors (with vinblastine or etoposide) squamous cell carcinomas and lymphomas
4.5.3 Toxicity minimally myelo- and immunosuppressive used in combination with other drugs Pulmonary Toxicity Cutaneous toxicity Hyperthermia, headache, nausea, vomiting
5 Microtubule Inhibitors
5.1 block assembly and disassembly of MTs
5.2 functions in metaphase
5.3 Vinca Alkaloids
5.3.1 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
5.4 Taxanes
5.4.1 Mechanism promote polymerization and stabilize MTs prevent breakdown
5.4.2 Therapeutics Paclitaxel and Docetaxel metastatic breast, ovarian, lung, head and neck. Docetaxel hormone-refractory prostate cancer
5.4.3 Toxicity Neutropenia, peripheral neuropathy, hypersensitivity
6 Topoisomerase Inhibitors
6.1 Topoisomerase mediate DNA strand breakage and resealing
6.1.1 Topo I breaks and seals single stranded
6.1.2 Topo II breaks and seals double stranded DNA
6.2 Epipodophyllotoxins
6.2.1 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
6.3 Camptothecin Analogs
6.3.1 Mechanism inhibit Topo I
6.3.2 Therapeutics Irinotecan advanced colon cancer lung, ovarian, cervical, brain tumors Topotecan ovarian and small cell lung cancer
6.3.3 Toxicity severe neutropenia and severe diarrhea
7 Hormones and Antagoists
7.1 used for hormone dependent neoplasms
7.1.1 breast and prostate cancer
7.2 glucocorticoids
7.2.1 treat lymphocytic leukemias and lymphomas
7.2.2 Mechanism inhibit mitosis in lymphocytes
7.2.3 no immunosuppression and well tolerated
7.2.4 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
7.3 Estrogen antagonists
7.3.1 breast cancer
7.4 Androgen antagonists
7.4.1 prostate cancer
7.5 Selective Estrogen-Receptor Modulators
7.5.1 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
7.6 Selective Estrogen-Receptor Downregulators
7.6.1 Fulvestrant Mechanism binds to ER, preventing dimerization Reduces number of ER molecules Therapeutics postmenopausal women with ER-positive metastatic breast cancer
7.7 Aromatase Inhibitors
7.7.1 inhibit aromatase enzyme, causing estrogen decrease
7.7.2 Aminoglutethamide weak inhibitor significant toxicity
7.7.3 Anastrozole potent and selective inhibitor ER-positive breast cancer in postmenopausal women
7.8 Prostate Cancer Treatments
7.8.1 Leuprolide (Lupron) and Goserelin (Zoladex) GnRH analogs inhibit release of LH and FSH Decreased Testosterone Production
7.8.2 Complete androgen ablation therapy involves combination of GnRH analogs and AR blockers
7.8.3 Flutamide and Bicalutamide nonsteroidal androgen-receptor blockers compete for androgen receptor and prevent its translocation to nucleus
8 Miscellaneous Agents
8.1 Hydroxyurea
8.1.1 inhibits ribonucleside diphosphate reductase converts ribonucleosides to deoxyribonucleosides
8.1.2 Therapeutics myeloproliferative neoplasms, polycythemia vera and essential thrombocythemia
8.2 Retinoids
8.2.1 treats acute promyelocytic leukemia
8.2.2 induces differentiation in leukemic promyelocytes
8.3 Arsenic Trioxide
8.3.1 treats relapsed APL
8.4 Thalidomide
8.4.1 treats multiple myeloma and myelodysplastic syndromes
8.5 Interferons
8.5.1 IF alpha for hairy cell leukemia, CML, AIDS relate Kaposi's sarcoma
8.6 Tyrosine Kinase Inhibitors
8.6.1 Imatinib inhibits Abl kinase, PDGFR and c-kit treats CML and GI tumor
8.6.2 Gefitinib and Erlotinib inhibit EGFR tyrosine kinase treats non-small cell lung cancer
8.7 Monoclonal Antibodies
8.7.1 Rituximab targets CD20 B-cell antigen Treats non-Hodgkin's Lymphoma
8.7.2 Trastuzumab antibody against HER2/neu treats HER2/neu-overexpressing breast cancer
8.7.3 Cetuximab antibody against EGFR1 (ErbB1 approved for EGFR-positive colorectal cancer

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