3. Cancer Pharmacology Part 1 Flashcards
What are genes that positively influence tumor formation such as RAS?
Oncogenes (overexpression)
What are genes that negatively impact tumor growth such as p53?
Tumor Suppressors (supression/knock out)
Cell Cycle Review First to Last Mitotic Phase (Cell division) = M phase Gap Phase 1= G1 Resting Phase= G0 Synthetic Phase = S Phase = DNA replication Gap Phase 2= G2 (end - back to M phase) G1 and G2 STOP inappropriate cell cycle progression via check points- either end in cell cycle arrest or entry into G0. Activation of oncogenes overrides (GF/RAS) which checkpoint and Inactivation of tumor suppressor genes (p53) overrides which checkpoint?
Activation of oncogenes overrides G1 arrest (restriction point to check mitotic division errors)
Inactivation of tumor suppressor genes overrides G2 (DNA replication checkpoint)
What is chemotherapy that is administered usually in advanced cancer with no alt. treatments or in advanced metastatic disease with goals of relieving tumor sx, improve quality of life and prolong time to tumor progression?
Primary Chemotherapy
What type of chemotherapy is used in patients who present with localized cancer for which alternative local therapies like surgery exist but which have been shown to be less than completely effective, given before surgery to shrink tumor?
Neoadjuvant Chemotherapy
What type of chemotherapy is used as an adjuvant to local therapy and administered after surgery to reduced incidence of local and systemic recurrence and improve overall survival of patients, prolonging disease free survival?
Adjuvant Chemotherapy
What type of chemotherapeutic resistance occurs as drug resistance in the absence of prior exposure to available standard agents, or d/t genomic instability of cancer such as p53 mutations?
Primary/Inherent Chemotherapeutic Resistance
What type of chemo resistance develops in response to exposure to a given cancer chemotherapeutic drug, or due to genetic change such as amplification or suppression of a particular gene?
Acquired Chemotherapeutic Drug Resistance
p-Glycoprotein- PGP (MDR1) expression is in tissues with barrier functions including kidney, liver, GI tract, they have pharmacological barrier sites at BBB and placenta blood barrier, high baseline expression of PGP correlates with primary/inherent resistance to natural products, and or can be overexpressed leading to acquired?
Drug resistance
Chemotherapy has limited selective toxicity kind of like a bull in a china shop- kills tumor and human cells without specificity. Therapeutic index is Toxic dose50/effective dose 50, chemo drugs have LOW therapeutic index which means small difference between effective and toxic doses, what doses are required to maximize cancer cell death?
HIGH doses are required to maximize rapid cancer cell death***
Normal cells are susceptible to adverse effects of chemotherapy such as bone marrow precurosors of blood cells causing myelosuppression and cytopenias, intestinal epithelial cells, oral mucosa, gondal cells (testes/ovaries), and what on the skin?
Hair follicles leading to alopecia
Alkylating agents transfer an alkyl groups (CH-CH3-CH3) to DNA leading to DNA cross linking, arrest occurs in late G1/ Sphase*, individual drugs vary in how they do this (cisplatin vs cyclophosphamide), what cells are the most susceptible?
Replicating cells** no effect on older-senscent cells
Some mechanisms of resistance to alkylating agents include decreased cellular transport of the drug (influx/efflux), increased expression of activity of glutathione and glutathione proteins (inactivates it), and increased capability to repair DNA lesions through increased expression and activity of DNA repair genes such as?
MGMT (O-methylguanine-DNA methyltransferase)
Side effects of alkylating agents primarily occur in rapidly growing tissue- including myelosuppression, GI tract- diarrhea, repro system, N/V, blistering at site of admin, and increased risk of secondary malignancies** such as?
Acute Myelogenous leukemia AML
Resistance to bis(chloroethyl) amines including cyclophosphamide mechlorethamine, melphalan and chlorambucil occurs via inc. expression of DNA repair enzymes MGMT, and inc. expression of glutathione, what agent is HIGHLY lipophilic which allows it to cross the BBB to treat glioblastomas?
Carmustine
What cancer agent mimics and or reduces the essential components needed for the formation of DNA, RNA, and proteins, arrest and or DNA damage occuring during S phase, replicating cells are the most susceptible?
Antimetabolites (MTX/cytarabine)
MOR for antimetabolites include inhibition of metabolism into active metabolites such as cytarabine and its active metabolity Ara-CTP, decreased drug transport, and decreased formation of poly glutamate metabolites by folyl polyglutamate synthase FPGS- important for pemetrexed, pralatrexate and?
Methotrexate
Adverse effects of antimetabolites include myelosuppression, N/V, diarrhea/mucositis (esp 5FU), hand foot syndrome which is painful erythema and swelling of the hands and feet (premetrexed), what is used as a ‘rescue’ for MTX toxicity?
Leucovorin (folinic acid)
What antimetabolite is the single most active agent for acute myelogenous leukemia AML, is a deoxycytidine analog converted to triphosphate metabolite (ara-CTP) which competitively binds DNA polymerase A (block DNA synthesis) and DNA polymerase B (blocks DNA repair), and it also is incorporated into DNA, interfereing with chain elongation and is incorporated into RNA?
Cytarabine - Antimetabolite
What antimetabolite is a purine antagonist inactive in parent form (azathioprine), metabolized by HGPRT to form monophosphate nucleotide 6-thioinosinic acid, which inhibits several enzymes of de novo purine nucleotide synthesis, triphosphate form is incorporated into RNA and DNA?
6-Mercaptopurine (6-MP)- purine antagonist
What class of cancer agents consists of tubulin polymerization inhibition (vinblastine/cristine/vinorelbine) and activation (paclitaxel***, docetaxel, cabazitaxel) and topoisomerase inhibitors (type 1 = topotecan/irinotecan, Type 2= etoposide)?
Natural products
Natural products have mechanisms of resistance that include point mutations in drug binding pockets (topoisomerase 1/2) and what mediated drug efflux?
p-glycoprotein PGP
Adverse effects of natural products (tubulin polymerization inhib/enhance and topoisomerase 1/2 inhib) include myelosuppression, N/V, hypersensitivity (allergic reaction) seen with paclitaxel and docetaxel, diarrhea assoc with topotecan and irnotecan and neurotoxicity MC with?
Vincrisitine (glove and stocking neuropathy)
Paclitaxel (taxane natural product) enhances tubulin polymerization, Vinblastine (vinca alkaloid natrual product) inhibits tubulin polymerase distrupting assembly of microtubules, p-glycoprotein expression often confers resistance to natural products, besides which agent which avoids the MOR?
Cabazitaxel (taxane)
