Disease relevance of Calicheamicin

• Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 antibody conjugated to the anticancer agent calicheamicin, approved for the treatment of CD33+-relapsed acute myeloid leukemia [1].
• Targeted therapy of experimental renal cell carcinoma with a novel conjugate of monoclonal antibody 138H11 and calicheamicin thetaI1 [2].
• Here, we describe the first successful use of calicheamicin theta(I)1 for targeted chemotherapy in a clinically relevant syngeneic metastasis model [3].
• Potent and specific antitumor efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B-cell lymphoma [4].
• We asked whether a conjugate of the cytotoxic antibiotic N-acetyl gamma calicheamicin dimethyl hydrazide (CalichDMH) and an antibody recognizing Lewis(y) (Le(y)) antigen could eliminate carcinomas that express Le(y) [5].

High impact information on Calicheamicin

• Whereas GCN4 binding is not inhibited by the calicheamicin aryltetrasaccharide, binding of CAP to its DNA target is significantly inhibited, and calicheamicin cutting of DNA at the center of the CAP-DNA complex site is strongly reduced by protein binding [6].
• Supercoiling affects the accessibility of glutathione to DNA-bound molecules: positive supercoiling inhibits calicheamicin-induced DNA damage [7].
• We demonstrate here that the enediyne calicheamicin gamma1I, a strand-breaking agent specific to the minor groove, causes approximately 50% more damage in negatively supercoiled plasmid DNA than in DNA with positive superhelicity [7].
• Calicheamicin gamma 1I, a member of the DNA-cleaving enediyne class of anticancer antibiotics, binds to specific DNA sequences through an aryltetrasaccharide domain [8].
• Because of the recognition sites reported in the original cleavage paper, calicheamicin has been assumed to recognize oligopyrimidine DNA sequences containing G-C base pairs [9].

Chemical compound and disease context of Calicheamicin

• Removal by human apurinic/apyrimidinic endonuclease 1 (Ape 1) and Escherichia coli exonuclease III of 3'-phosphoglycolates from DNA treated with neocarzinostatin, calicheamicin, and gamma-radiation [10].

Biological context of Calicheamicin

• We report the development of a mouse B cell-depleting immunoconjugate (anti-CD22 monoclonal antibody [mAb] conjugated to calicheamicin) and its in vivo use to characterize the kinetics of CD22+ B-cell depletion and reconstitution in murine primary and secondary lymphoid tissues [11].
• The overexpression of Bcl-x(L) or Bcl-2 strongly inhibited calicheamicin-induced apoptosis [12].
• Knockout of Bax abrogated cell death after calicheamicin treatment [12].
• Footprinting and chemical modification studies have identified the (T-C-C-T).(A-G-G-A) sequence as a preferred calicheamicin gamma 1I binding site and established the importance of the 5'-guanine residue as critical for high affinity binding [13].
• With longer calicheamicin exposure, genes involved in chromatin arrangement, DNA repair and/or oxidative damage, DNA synthesis and cell cycle checkpoint control as well as other nuclear proteins were all differentially expressed [14].

Anatomical context of Calicheamicin

• In a phase II study of Mylotarg (CMA-676, gemtuzumab ozogamicin), which consists of a CD33 antibody linked to calicheamicin, saturation and internalization by leukemic and normal myeloid cells were analyzed in 122 patients with relapsed AML [15].
• This places caspase activation upstream of the mitochondria and indicates that calicheamicin-triggered apoptosis is enhanced through death receptor-independent activation of the caspase cascade, that is, an amplification loop that is required for full activation of the mitochondrial pathway [12].
• PURPOSE: Gemtuzumab ozogamicin (Mylotarg; Wyeth Laboratories, Philadelphia, PA) consists of a semisynthetic derivative of calicheamicin, a cytotoxic antibiotic linked to a recombinant monoclonal antibody directed against the CD33 antigen present on leukemic myeloblasts in most patients with acute myeloid leukemia (AML) [16].
• Monoclonal antibodies to the myeloid stem cells: therapeutic implications of CMA-676, a humanized anti-CD33 antibody calicheamicin conjugate [17].
• Sensitivity of fibroblasts derived from ataxia-telangiectasia patients to calicheamicin gamma 1I [18].

Associations of Calicheamicin with other chemical compounds

• DNA fragments produced by CAL and ESP C in the nucleosome core occurred with a 10-11-nucleotide periodicity similar to that produced by DNase I, while damage produced by NCS and ESP A1 appeared to be limited to the terminal portions of the core DNA [19].
• Antibody-targeted chemotherapy with the calicheamicin conjugate hu3S193-N-acetyl gamma calicheamicin dimethyl hydrazide targets Lewisy and eliminates Lewisy-positive human carcinoma cells and xenografts [5].
• In common with other free-radical generating agents such as bleomycin and ionizing radiation, treatment with calicheamicin gamma 1I reveals AT derived lines to be 6-fold more sensitive to this drug when compared to controls [18].
• Gemtuzumab ozogamicin is an antibody-chemotherapeutic conjugate characterized as antibody-targeted chemotherapy, consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic agent, N-acetyl-gamma calicheamicin DMH [20].
• The data on cell survival (D10 values) show that they are hypersensitive to adriamycin (2-3-fold increase), etoposide (3-fold for V-G8 and 6-fold for V-E5 and V-C4), calicheamicin gamma 1I (4-fold) and streptonigrin (3-fold for V-G8 and V-C4, and 12-fold for V-E5) [21].

Gene context of Calicheamicin

• In contrast, we found that calicheamicin-induced strand breaks activated ATM more efficiently than IR and that ATM activation correlated with the relative DSB induction by these agents [22].
• Here, we show by the use of the unconjugated drug that calicheamicin-induced apoptosis is independent from death-receptor/FADD-mediated signals [12].
• Using gemtuzumab ozogamicin (Mylotarg, a humanized anti-CD33 antibody conjugated with calicheamicin, the effectiveness of in vivo ablation of CD33+ cells to treat patients with AML was borne out by the portion of patients who achieved remission [23].
• In addition, the repair kinetics of the DSBs induced by calicheamicin gamma1 was delayed both in PARP-1-proficient cells pretreated with the PARP-1 inhibitor and in PARP-1-deficient cells [24].
• While searching for a DNA-PK-independent end-joining activity, we found that the pretreatment of DNA-PK-proficient and -deficient rodent cells with an inhibitor of the poly(ADP-ribose) polymerase-1 enzyme (PARP-1) led to increased cytotoxicity of the highly efficient DNA double-strand breaking compound calicheamicin gamma1 [24].

Analytical, diagnostic and therapeutic context of Calicheamicin

• Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies [25].
• We have investigated the mode of action of calicheamicin in living cells by using oligonucleotide microarrays to monitor its effects on gene expression across the entire yeast genome [14].
• Cloning and sequence analysis of AT2433 gene cluster and comparison of this locus with that encoding for rebeccamycin and the gene cluster encoding calicheamicin present an opportunity to study the aminodideoxypentose biosynthesis via comparative genomics [26].
• Calicheamicin derivatives conjugated to monoclonal antibodies: determination of loading values and distributions by infrared and UV matrix-assisted laser desorption/ionization mass spectrometry and electrospray ionization mass spectrometry [27].
• A re-examination of the circular dichroism of the calicheamicin enediyne/dienone chromophoric interaction [28].

References