#chemotherapy

Animal Tissue Culture 3

EdU followed by doxorubicin treatment selectively targets:

Sequential application of EdU labeling followed by doxorubicin treatment represents strategy to track and preferentially eliminate newly dividing cells. EdU pulse marks cells traversing S phase with alkyne-modified nucleotide that persists in DNA of daughter cells, identifiable via click chemistry fluorescent azide. When doxorubicin subsequently administered, antineoplastic action via topoisomerase II trapping and generation of reactive oxygen species is most pronounced in actively cycling population where chromatin decondensed, replication forks active, and topoisomerase IIalpha expression hi

Ref: Thorn et al Doxorubicin S-phase targeting; Salic & Mitchison EdU newly dividing cells detection for chemosensitivity studies.

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Animal Tissue Culture 3

Doxorubicin induces cell death mainly by:

Doxorubicin, anthracycline antibiotic isolated from Streptomyces peucetius subsp. caesius, induces cytotoxicity via dual mechanisms of DNA damage and oxidative stress. Planar tetracyclic chromophore intercalates between DNA base pairs preferentially at CpG sequences increasing helical length and inhibiting topoisomerase IIalpha by trapping covalent enzyme-DNA cleavage complex preventing resealing of transient double-strand breaks introduced during replication, leading to activation of ATM kinase, phosphorylation of histone H2AX at serine139 forming gamma-H2AX foci, p53 accumulation, and mitoch

Ref: Thorn et al PharmGKB Doxorubicin topoisomerase II ROS; Gewirtz DA Biochem Pharmacol 1999 Doxorubicin DNA damage ROS mechanisms.

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Membrane Transportation

Which ABC transporter is associated with multidrug resistance in cancer?

Cancer multidrug efflux is dominated not by CFTR or P-type ATPases but by ABC transporters that expel amphipathic chemotherapeutics from cytoplasm. ABCB1 P-glycoprotein MDR1 is best studied, overexpressed in colonic, renal, adrenocortical carcinomas and after chemotherapy induction in leukemia, lymphoma and breast cancer. Its polyspecific hydrophobic binding chamber accommodates doxorubicin, daunorubicin, vinblastine, vincristine, paclitaxel and etoposide causing cross-resistance. ABCC1 MRP1 exports glutathione conjugates of drugs, ABCG2 BCRP expels mitoxantrone and topotecan. Expression corre

Ref: Gottesman et al., Annu Rev Med 2002, MDR in cancer; Szakacs et al., Nat Rev Drug Discov 2006.

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Cancer

One mechanism of chemotherapy resistance is

Defective apoptotic machinery, is consistent with established principles of cell signaling, receptor pharmacology and cellular regulation. Experimental measurements of binding parameters, genetic loss-of-function studies and pharmacological interventions all converge on the same interpretation. Related options address neighboring concepts but do not satisfy the precise criterion stated in the question.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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