Cellular parameters that affect GO efficacy
| Factor . | Comment . |
|---|---|
| Uptake of CD33/GO complexes | |
| Receptor-mediated uptake | |
| CD33 expression levels | Good evidence supporting quantitative relationship from experimental and correlative studies83,90,91,125 ; expression levels associated with cytogenetic risk of AML126 and CD33 SNPs127 |
| CD33 saturation | In vitro evidence linking reduced CD33 saturation to reduced GO cytotoxicity128 |
| CD33 internalization | Relatively slow process, controlled by intracellular tyrosine motifs91 and likely tyrosine phosphorylation status of CD33 |
| Reexpression of CD33 binding sites | Surface CD33 levels return to pretreatment levels within 72 hours after CD33 antibody administration104 ; could contribute to amount of internalized GO, in particular if GO is administered in fractionated doses. |
| Non–receptor-mediated uptake | Suggested by experimental studies93 ; clinical role unknown |
| Intracellular trafficking of GO | Hypothetical |
| Activation of GO | Low pH in lysosomes required (R.B.W., unpublished data, December 2004) |
| Extrusion of GO | |
| ABC family of drug transporters | Good evidence from experimental and correlative studies for role of P-glycoprotein and multidrug resistance-associated protein 184,89,90 ; role of other transporters unknown |
| Induction of cytotoxicity | |
| Generation of SS- and DS-DNA breaks | Hypersensitivity of cell lines with defects in DNA repair to calicheamicins85,86 |
| Mitochondrial pathways of apoptosis | Good experimental evidence for role of pro- and antiapoptotic Bcl-2 protein family members84 |
| Other downstream pro- or antiapoptotic signaling pathways | Not examined in detail |
| Cell-cycle status | Limited in vitro data suggesting that resting cells are relatively less susceptible to GO93 |
| Factor . | Comment . |
|---|---|
| Uptake of CD33/GO complexes | |
| Receptor-mediated uptake | |
| CD33 expression levels | Good evidence supporting quantitative relationship from experimental and correlative studies83,90,91,125 ; expression levels associated with cytogenetic risk of AML126 and CD33 SNPs127 |
| CD33 saturation | In vitro evidence linking reduced CD33 saturation to reduced GO cytotoxicity128 |
| CD33 internalization | Relatively slow process, controlled by intracellular tyrosine motifs91 and likely tyrosine phosphorylation status of CD33 |
| Reexpression of CD33 binding sites | Surface CD33 levels return to pretreatment levels within 72 hours after CD33 antibody administration104 ; could contribute to amount of internalized GO, in particular if GO is administered in fractionated doses. |
| Non–receptor-mediated uptake | Suggested by experimental studies93 ; clinical role unknown |
| Intracellular trafficking of GO | Hypothetical |
| Activation of GO | Low pH in lysosomes required (R.B.W., unpublished data, December 2004) |
| Extrusion of GO | |
| ABC family of drug transporters | Good evidence from experimental and correlative studies for role of P-glycoprotein and multidrug resistance-associated protein 184,89,90 ; role of other transporters unknown |
| Induction of cytotoxicity | |
| Generation of SS- and DS-DNA breaks | Hypersensitivity of cell lines with defects in DNA repair to calicheamicins85,86 |
| Mitochondrial pathways of apoptosis | Good experimental evidence for role of pro- and antiapoptotic Bcl-2 protein family members84 |
| Other downstream pro- or antiapoptotic signaling pathways | Not examined in detail |
| Cell-cycle status | Limited in vitro data suggesting that resting cells are relatively less susceptible to GO93 |
SNP indicates single-nucleotide polymorphism; SS, single-stranded; and DS, double-stranded.