11: Cancer Lecture III Flashcards
DNA Intercalating Agents are anti-tumor _______ produced by Streptomyces. They bind to DNA through intercalation between specific bases & cause DNA strand _______, which can block synthesis of DNA, RNA or both.
DNA Intercalating Agents are anti-tumor antibiotics produced by Streptomyces. They bind to DNA through intercalation between specific bases & cause DNA strand breaks, which can block synthesis of DNA, RNA or both.
Specific DNA Intercalating Agents–Dactinomycin (also known as Actinomycin D):
anticancer antibiotic derived from Streptomyces
intercalates between adjacent G-C base pairs
interferes with DNA-dependent RNA polymerase, causing inhibition of DNA _______
also causes _______ strand breaks** in DNA
used for treatment of _______ tumor, _______ sarcoma and _______ sarcoma in children
Toxicity is anorexia, nausea, and vomiting. Also gives hematopoietic suppression with pancytopenia.
Specific DNA Intercalating Agents–Dactinomycin (also known as Actinomycin D):
anticancer antibiotic derived from Streptomyces
intercalates between adjacent G-C base pairs
interferes with DNA-dependent RNA polymerase, causing inhibition of DNA transcription
also causes single strand breaks** in DNA
used for treatment of Wilm’s tumor, rhabdomyosarcoma and Ewing’s sarcoma in children
Toxicity is anorexia, nausea, and vomiting. Also gives hematopoietic suppression with pancytopenia.
Tha _______ are DNA intercalating agents that include Daunorubicin, Doxorubicin, Epirubicin, Idarubicin.
Tha anthracyclines are DNA intercalating agents that include Daunorubicin, Doxorubicin, Epirubicin, Idarubicin.
Doxorubicin and other anthracycline drugs intercalate between DNA base pairs. Anthracyclines are reduced to intermediates that donate electrons to oxygen to form superoxide. Superoxide then reacts with itself to make _______ _______, which is cleaved in the presence of iron to form the destructive _______ radical that cleaves DNA.
Doxorubicin and other anthracycline drugs intercalate between DNA base pairs. Anthracyclines are reduced to intermediates that donate electrons to oxygen to form superoxide. Superoxide then reacts with itself to make hydrogen peroxide, which is cleaved in the presence of iron to form the destructive hydroxyl radical that cleaves DNA.
Specific DNA Intercalating Agents (Anthracyclines)–Doxorubicin:
has _______ clinical spectrum; one of the most widely used anticancer drugs
used for treatment of sarcomas, breast and lung carcinomas, and lymphomas
Specific DNA Intercalating Agents (Anthracyclines)–Doxorubicin:
has broad clinical spectrum; one of the most widely used anticancer drugs
used for treatment of sarcomas, breast and lung carcinomas, and lymphomas
Specific DNA Intercalating Agents (Anthracyclines)–Daunorubicin and Idarubicin:
used in combination with Ara-C (Cytarabine) antimetabolite for treatment of _______
Specific DNA Intercalating Agents (Anthracyclines)–Daunorubicin and Idarubicin:
used in combination with Ara-C (Cytarabine) antimetabolite for treatment of AML
Specific DNA Intercalating Agents (Anthracyclines)–Epirubicin:
used in combo regimen (FEC) for treatment of metastatic _______ cancer
Specific DNA Intercalating Agents (Anthracyclines)–Epirubicin:
used in combo regimen (FEC) for treatment of metastatic breast cancer
Anthracyclines Toxicity:
Dose-limiting _______!
_______ is an iron-chelating agent that blocks the formation of free radicals and protects against cardiotoxicity of anthracyclines such as doxorubicin.
Anthracyclines give _______ so do not give to patients with heart issues!
Neutropenia, Stomatitis, alopecia
Anthracyclines Toxicity:
Dose-limiting cardiotoxicity (cardiomyopathy)!
Dexrazoxane is an iron-chelating agent that blocks the formation of free radicals and protects against cardiotoxicity of anthracyclines such as doxorubicin.
Anthracyclines give cardiomyopathy so do not give to patients with heart issues!
Neutropenia, Stomatitis, alopecia
Specific DNA Intercalating Agents–Bleomycin:
a mixture of two peptides obtained from Streptomyces
binds to DNA, induces _______- and _______-stranded DNA breaks**
cell cycle specific, acts in the _______ phase of the cell cycle**
Specific DNA Intercalating Agents–Bleomycin:
a mixture of two peptides obtained from Streptomyces
binds to DNA, induces single- and double-stranded DNA breaks**
cell cycle specific, acts in the G2 phase of the cell cycle**
Specific DNA Intercalating Agents–Bleomycin:
used as a component of PEB combo regimen for treatment of _______ carcinomas or as a component of ABVD regimen for _______ disease
also effective against squamous cell carcinomas
Toxicity
dose-related _______ toxicity (_______ fibrosis)** so do not give Bleomycin to smokers
minimally myelosuppressive
cutaneous toxicity (hyperpigmentation, hyperkeratosis, erythema)
Specific DNA Intercalating Agents–Bleomycin:
used as a component of PEB combo regimen for treatment of testicular carcinomas or as a component of ABVD regimen for Hodgkin’s disease
also effective against squamous cell carcinomas
Toxicity
dose-related pulmonary toxicity (pulmonary fibrosis)** so do not give Bleomycin to smokers
minimally myelosuppressive
cutaneous toxicity (hyperpigmentation, hyperkeratosis, erythema)
Microtubule Inhibitors are plant natural products that bind to tubulin and interfere with microtubule function. Microtubule Inhibitors cause mitotic _______ (act in the _______ phase of cell cycle).
Microtubles are important for _______ formation and chromosome segregation during mitosis so microtubule inhibitors are cell cycle specific in the M phase.
Microtubule Inhibitors are plant natural products that bind to tubulin and interfere with microtubule function. Microtubule Inhibitors cause mitotic arrest (act in the M phase of cell cycle).
Microtubles are important for spindle formation and chromosome segregation during mitosis so microtubule inhibitors are cell cycle specific in the M phase.
Specific microtubule Inhibitors (Vinca Alkaloids)–Vinblastine, Vincristine:
bind to tubulin, and prevent _______ of tubulin into microtubules
Vinblastine is a component of combination regimen (ABVD) for _______ lymphoma
Vincristine is used with glucocorticoids in the treatment of childhood _______; also a component of MOPP regimen for _______ lymphoma
Specific microtubule Inhibitors (Vinca Alkaloids)–Vinblastine, Vincristine:
bind to tubulin, and prevent polymerization (assembly) of tubulin into microtubules
Vinblastine is a component of combination regimen (ABVD) for Hodgkin’s lymphoma
Vincristine is used with glucocorticoids in the treatment of childhood ALL; also a component of MOPP regimen for Hodgkin’s lymphoma
Specific microtubule Inhibitors (Vinca Alkaloids)–Vinblastine, Vincristine:
Vinblastine- myelosuppression, nausea, vomiting
Vincristine- dose-limiting _______** (peripheral _______); relatively low toxicity in the bone marrow
Resistance: amplification of P-glycoprotein or mutations in tubulin resulting in reduced binding of the drugs to their target.
Specific microtubule Inhibitors (Vinca Alkaloids)–Vinblastine, Vincristine:
Vinblastine- myelosuppression, nausea, vomiting
Vincristine- dose-limiting neurotoxicity** (peripheral neuropathy); relatively low toxicity in the bone marrow
Resistance: amplification of P-glycoprotein or mutations in tubulin resulting in reduced binding of the drugs to their target.
Specific microtubule Inhibitors (Taxanes)–Paclitaxel, Docetaxel:
bind to tubulin, and prevent _______ of microtubules
Paclitaxel and docetaxel are components of regimens used for treatment of metastatic _______, ovarian, lung, and head and neck cancers
Docetaxel is useful against hormone-refractory prostate cancer
Specific microtubule Inhibitors (Taxanes)–Paclitaxel, Docetaxel:
bind to tubulin, and prevent depolymerization (dissasembly) of microtubules
Paclitaxel and docetaxel are components of regimens used for treatment of metastatic breast, ovarian, lung, and head and neck cancers
Docetaxel is useful against hormone-refractory prostate cancer
Specific microtubule Inhibitors (Taxanes)–Paclitaxel, Docetaxel:
Mitotic spindles are formed from microtubules in mitosis.
Vinca alkaloids block microtubule _______ and Taxanes block microtubule _______, both are required for chromosome segregation so they prevent mitosis.
Toxicity of (Taxanes)–Paclitaxel, Docetaxel: neutropenia, peripheral _______**, hypersensitivity reactions
Specific microtubule Inhibitors (Taxanes)–Paclitaxel, Docetaxel:
Mitotic spindles are formed from microtubules in mitosis.
Vinca alkaloids block microtubule assembly and Taxanes block microtubule dissasembly, both are required for chromosome segregation so they prevent mitosis.
Toxicity of (Taxanes)–Paclitaxel, Docetaxel: neutropenia, peripheral neuropathy**, hypersensitivity reactions
Topoisomerase Inhibitors:
Topoisomerases mediate DNA strand breakage and resealing during replication or transcription of DNA. Topoisomerase I breaks and reseals _______-stranded DNA, whereas topoisomerase II breaks and reseals _______-stranded DNA. Inhibitors of topoisomerases cause permanent DNA strand breaks by preventing the _______ of nicked strands of DNA.
Topo 1 = fixes _______ breaks (Irinotecan, Topotecan inhibit Topo1)
Topo2 = fixes _______ breaks (Etoposide, Teniposide inhibit Topo2)
Topoisomerase Inhibitors:
Topoisomerases mediate DNA strand breakage and resealing during replication or transcription of DNA. Topoisomerase I breaks and reseals single-stranded DNA, whereas topoisomerase II breaks and reseals double-stranded DNA. Inhibitors of topoisomerases cause permanent DNA strand breaks by preventing the resealing of nicked strands of DNA.
Topo 1 = fixes ssDNA breaks (Irinotecan, Topotecan inhibit Topo1)
Topo2 = fixes dsDNA breaks (Etoposide, Teniposide inhibit Topo2)
Specific Topoisomerase Inhibitors (Epipodophyllotoxins)–Etoposide, Teniposide:
inhibit topoisomerase _______, cells have an accumulation of _______ breaks with this drug
Etoposide has broad clinical spectrum; used for treatment of testicular carcinoma, lung cancer, and non-Hodgkin’s lymphoma
Teniposide mainly used for acute lymphoblastic leukemia (ALL)
Toxicity: dose-limiting myelosuppression (neutropenia), oral mucositis.
Remember that myelosuppression = bone marrow suppression
Specific Topoisomerase Inhibitors (Epipodophyllotoxins)–Etoposide, Teniposide:
inhibit topoisomerase II, cells have an accumulation of dsDNA breaks with this drug
Etoposide has broad clinical spectrum; used for treatment of testicular carcinoma, lung cancer, and non-Hodgkin’s lymphoma
Teniposide mainly used for acute lymphoblastic leukemia (ALL)
Toxicity: dose-limiting myelosuppression (neutropenia), oral mucositis.
Remember that myelosuppression = bone marrow suppression
Specific Topoisomerase Inhibitors (Camptothecin Analogs)–Irinotecan, Topotecan:
inhibit topoisomerase _______ & give accumulation of _______ breaks.
Irinotecan is approved for treatment of advanced colorectal cancer; also used for lung, ovarian, cervical and brain tumors
Topotecan is indicated for treatment of ovarian and small cell lung cancer
Toxicity: severe neutropenia, severe diarrhea
Specific Topoisomerase Inhibitors (Camptothecin Analogs)–Irinotecan, Topotecan:
inhibit topoisomerase I & give accumulation of ssDNA breaks.
Irinotecan is approved for treatment of advanced colorectal cancer; also used for lung, ovarian, cervical and brain tumors
Topotecan is indicated for treatment of ovarian and small cell lung cancer
Toxicity: severe neutropenia, severe diarrhea
Hormones and their Antagonists are used for treatment of hormone-dependent neoplasms.
Hormonal therapy is useful in three clinical settings:
- _______ and leukemias
- _______ cancer
- _______ cancer
Hormones and their Antagonists are used for treatment of hormone-dependent neoplasms.
Hormonal therapy is useful in three clinical settings:
- Lymphomas and leukemias
- Breast cancer
- Prostate cancer
Hormone Therapy for Lymphomas and Leukemias
Glucocorticoids: Prednisone, Dexamethasone have cytotoxic effects on _______; inhibit mitosis in lymphocytes.
Prednisone plus vincristine produce remission in patients with _______.
Prednisone is also a component of combination regimens (MOPP and CHOP) for Hodgkin’s and non-Hodgkin’s _______
Dexamethasone is used to reduce edema following radiation therapy of brain tumors
Hormone Therapy for Lymphomas and Leukemias
Glucocorticoids: Prednisone, Dexamethasone have cytotoxic effects on lymphocytes; inhibit mitosis in lymphocytes.
Prednisone plus vincristine produce remission in patients with ALL.
Prednisone is also a component of combination regimens (MOPP and CHOP) for Hodgkin’s and non-Hodgkin’s lymphomas
Dexamethasone is used to reduce edema following radiation therapy of brain tumors
Hormone Therapy for Breast Cancer
Breast cancer is usually estrogen-dependent and can be suppressed by administration of estrogen antagonists
Anti-estrogen therapy includes
Selective Estrogen-Receptor Modulators (SERMs): _______
Selective Estrogen-Receptor Downregulators (SERDs): _______
Aromatase Inhibitors (AIs): Aminoglutethamide, Anastrozole, Letrozole, Exemestane
Hormone Therapy for Breast Cancer
Breast cancer is usually estrogen-dependent and can be suppressed by administration of estrogen antagonists
Anti-estrogen therapy includes
Selective Estrogen-Receptor Modulators (SERMs): Tamoxifen
Selective Estrogen-Receptor Downregulators (SERDs): Fulvestrant
Aromatase Inhibitors (AIs): Aminoglutethamide, Anastrozole, Letrozole, Exemestane
Selective Estrogen-Receptor Modulators (SERMs): Tamoxifen
Tamoxifen competes with estrogen for its receptor and forms an inactive receptor complex so it _______ estrogen binding and activity.
used for treatment of ER-_______** early-stage and metastatic breast cancer
used for _______** of breast cancer in high risk women (family history)
Toxicity:
hot flushes, hair loss, nausea and vomiting
weak _______** of ER in endometrium; increased risk of endometrial _______ and thromboembolism.
So Tamoxifen is antagonist in the _______, but weak agonist in the _______ & increases chance of endometrial cancer!
Selective Estrogen-Receptor Modulators (SERMs): Tamoxifen
Tamoxifen competes with estrogen for its receptor and forms an inactive receptor complex so it blocks estrogen binding and activity.
used for treatment of ER-positive** early-stage and metastatic breast cancer
used for prevention** of breast cancer in high risk women (family history)
Toxicity:
hot flushes, hair loss, nausea and vomiting
weak agonist** of ER in endometrium; increased risk of endometrial cancer and thromboembolism.
So Tamoxifen is antagonist in the breast, but weak agonist in the endometrium & increases chance of endometrial cancer!
Selective Estrogen-Receptor Downregulators (SERDs): Fulvestrant
Fulvestrant is the first FDA approved SERD binds to ER with a much _______ affinity (>100 fold) than tamoxifen and inhibits hormone-receptor complex formation
also _______ ER expression (that’s why called downregulateor)
approved for postmenopausal women with ER-_______** metastatic breast cancer
Selective Estrogen-Receptor Downregulators (SERDs): Fulvestrant
Fulvestrant is the first FDA approved SERD binds to ER with a much higher affinity (>100 fold) than tamoxifen and inhibits hormone-receptor complex formation
also reduces ER expression (that’s why called downregulateor)
approved for postmenopausal women with ER-positive** metastatic breast cancer
Aromatase Inhibitors (AIs) inhibit the enzyme aromatase, which is necessary for estrogen synthesis. AIs include: Aminoglutethamide, Anastrozole, Letrozole, Exemestane.
AIs cause profound estrogen _______ in postmenopausal women so very good breast cancer treatment.
Aromatase acts on either testosterone or androstenedione!
When Aromatase acts on Androstenedione, _______ is formed.
When Aromatase acts on Testosterone, _______ is formed.
Aromatase acts on ovary in premenapausal women & in the peripheral tissues of post menapausal women.
Aromatase activity is increased in breast cancer.
Aromatase Inhibitors (AIs) inhibit the enzyme aromatase, which is necessary for estrogen synthesis. AIs include: Aminoglutethamide, Anastrozole, Letrozole, Exemestane.
AIs cause profound estrogen deprivation in postmenopausal women so very good breast cancer treatment.
Aromatase acts on either testosterone or androstenedione!
When Aromatase acts on Androstenedione, Estrone is formed.
When Aromatase acts on Testosterone, Estradiol is formed.
Aromatase acts on ovary in premenapausal women & in the peripheral tissues of post menapausal women.
Aromatase activity is increased in breast cancer.
