Disease relevance of C11280

• We describe the in vitro and in vivo properties of monoclonal antibody (mAb)-drug conjugates consisting of the potent synthetic dolastatin 10 analogs auristatin E (AE) and monomethylauristatin E (MMAE), linked to the chimeric mAbs cBR96 (specific to Lewis Y on carcinomas) and cAC10 (specific to CD30 on hematological malignancies) [1].
• Phase II study of dolastatin-10 in patients with hormone-refractory metastatic prostate adenocarcinoma [2].
• We compared uptake and efflux of radiolabeled dolastatin 10 and vinblastine in human Burkitt lymphoma CA46 cells to gain an understanding of the greater cytotoxicity of the peptide [3].
• Symplostatin 1, an analog of dolastatin 10, was recently isolated from cyanobacteria of the genus Symploca [4].
• Dolastatin-10 in metastatic melanoma: a phase II and pharmokinetic trial of the California Cancer Consortium [5].

High impact information on C11280

• RESULTS: In the three B cell lines, dolastatin 10 was more effective than dolastatin 15 [6].
• Complete inhibition of human bone marrow cell colony formation was observed at concentrations of 10-100 pg/mL for dolastatin 10 and 1000-10,000 pg/mL for dolastatin 15 [7].
• We have investigated the ability of another antineoplastic drug, dolastatin 10, in inducing Bcl2 phosphorylation and apoptosis [8].
• Characterization of the interaction of cryptophycin 1 with tubulin: binding in the Vinca domain, competitive inhibition of dolastatin 10 binding, and an unusual aggregation reaction [9].
• The antimitotic depsipeptide cryptophycin 1 (CP1) was compared to the antimitotic peptide dolastatin 10 (D10) as an antiproliferative agent and in its interactions with purified tubulin [9].

Chemical compound and disease context of C11280

• In vivo, using a s.c. advanced-stage human ovarian carcinoma xenograft and equitoxic doses, greater activity was observed with dolastatin 10 (6.1-day growth delay) versus 0.4 days for dolastatin 15 [10].
• We studied the antitumor effects of dolastatin 10, its structural modification, auristatin PE (TZT-1027), and vincristine alone and in combination with bryostatin 1 on a human diffuse large cell lymphoma line (WSU-DLCL2) in vitro and in vivo [11].

Biological context of C11280

• Modeling studies revealed a highly favored binding site for dolastatin 10 at the + end of beta-tubulin in proximity to the exchangeable site GDP [12].
• A tripeptide segment of dolastatin 10 also effectively inhibits tubulin polymerization and GTP hydrolysis [13].
• Agents were added to triplicate wells, and cell count, viability, mitosis, and apoptosis were assessed after 24 h of incubation at 37 degrees C. Results showed that dolastatin 10 had no apparent inhibition of cell growth at concentrations less than 500 pg/ml [14].
• In initial experiments with 5 microM tubulin and 5 microM vinblastine, spongistatin 1 and dolastatin 10 both had IC50 values of 2 microM, whereas halichondrin B had an IC50 value of 5 microM [15].
• Dolastatin 10 is an unusual peptide of marine origin which binds to tubulin in the vinblastine/maytansine/phomopsin-binding region and potently inhibits mitosis [16].

Anatomical context of C11280

• Dolastatin 10, a potent antimitotic peptide from a marine animal, strongly inhibits microtubule assembly, tubulin-dependent GTP hydrolysis, and the binding of vinca alkaloids to tubulin [13].
• BACKGROUND: TZT-1027 is a synthetic dolastatin 10 analog with antineoplastic properties in various cell lines and tumor xenografts [17].
• For dolastatin 10, IC50 values of 0.4 and 0.5 nM were obtained with the L1210 and CHO cells, respectively [18].
• Dolastatin-10 has extremely potent in vitro activity against a variety of tumor cell lines [19].
• In vitro, dolastatin 10 was stable in mouse plasma for at least 24 hr at 37 degrees C. The drug was also highly protein-bound (> 81%) in human, dog, and mouse plasmas [20].

Associations of C11280 with other chemical compounds

• These results suggest that hemiasterlin is in close contact with alpha-tubulin and may span the interdimer interface so that it contacts the vinblastine- and dolastatin 10-binding sites believed to be in beta-tubulin [21].
• Auristatin PE or dolastatin 10 were added to triplicate wells and cell count and viability were assessed after 24, 48 and 72 h [22].
• Symplostatin 1 (2), like dolastatin 10 (1), is a potent microtubule inhibitor [23].
• BACKGROUND: TZT-1027 (Soblidotin), a newly synthesized dolastatin 10 derivative that depolymerizes microtubules, has potent antitumor activity [24].
• The latter represents a combination of stilbene 1a with the des-Doe tetrapeptide unit of the powerful tubulin assembly inhibitor dolastatin 10 [25].

Gene context of C11280

• Role of P-glycoprotein in dolastatin 10 resistance [26].
• While these findings suggested the involvement of the P-glycoprotein (P-gp) in dolastatin 10 resistance, we performed similar studies in a CHO cell line transfected with the human mdr1 cDNA [26].
• CONCLUSIONS: These findings suggest that dolastatin 10 has potent activity against SCLC and that the modulation of apoptotic pathways deserves further evaluation as an anticancer strategy [27].
• However, upon treatment of cells with a combination of bryostatin 1 and dolastatin 10 or auristatin PE, the induction of cIAP-1 was abolished, leading to a significant increase in apoptosis [28].
• WSU-DLCL2 cells were negative for p53 protein expression, upon treatment with Bryo1 or Dol10, the expression of p53 was weak and moderate with the Bryo1/Dol10 combination [29].

Analytical, diagnostic and therapeutic context of C11280

• Dolastatin 10 is a highly cytotoxic antimitotic peptide in phase II clinical trials [3].
• Similar changes in PtK1 cells were observed after treatment with equivalent toxic concentrations of the antimitotic agents colchicine, vinblastine, halichondrin B, and dolastatin 10 [15].
• Bound drug was stable in centrifugal gel filtration, column gel filtration, and high performance liquid chromatography gel filtration, but the bound drug could be displaced by an active isomer of dolastatin 10 [30].
• The biosynthetic peptide dolastatin 10 is currently in phase I and II cancer clinical trials [31].
• We performed a Phase II trial of Dolastatin-10, 400 microg/m2 in patients with advanced melanoma who had received no prior chemotherapy [5].

References