Table 4.

Main findings on the GO action mechanism.

GO Targeting Mechanism
GO is targeted rapidly and explicitly to CD33+ cells, forming the GO-CD33 immune complex. Internalization of GO is dependent on the number of CD33 molecules on the cell surface.
Endocytosis and Calicheamicin Release
The GO-CD33 immune complex is endocytosed, leading to fusion with a lysosome. Calicheamicin derivative is released from the antibody in the acidic lysosomal environment. GO incorporates a stable acid-hydrolyzable linker that efficiently degrades the lysosome.
Calicheamicin Activation and Nucleus Entry
Released calicheamicin is reduced to a reactive 1,4-dehydrobenzene di-radical. The di-radical can enter the nucleus, causing DNA damage through hydrogen atom abstraction. DNA damage results in single- and double-strand cleavage
Cellular Response and Apoptosis
Calicheamicin-induced DNA damage causes cell cycle arrest in the G2/M phase. Severe damage leads to apoptosis and cell death through the mitochondrial route. Proapoptotic activation of Bak and Bax, followed by caspase 3 activation, induces cell apoptosis.
DNA Repair Mechanisms
Calicheamicin-induced double-strand breaks initiate DNA repair. Repair protein ATM/ATR and DNA-dependent protein kinase (DNA-PK) are activated. ATM induces cell cycle arrest in G2/M, activating cyclin B1 and phosphorylating kinases Chk1 and Chk2. DNA-PK phosphorylates H2AX, recruiting DNA damage repair proteins.
Multidrug Resistance (MDR)
MDR, mediated by ATP-dependent drug transporters (e.g., P-glycoprotein, PGP), is linked to preclinical responses to GO therapy. Patients with higher PGP function and multidrug resistance protein 1 (MrP1) show resistance to GO, persistence of blasts in bone marrow, and difficulty achieving complete remission. In vitro, MDR is associated with reduced GO-induced apoptosis.