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Targeted alpha therapy approach to the management of pancreatic cancer.

Allen BJ, Rizvi SM, Qu CF, Smith RC - Cancers (Basel) (2011)

Bottom Line: In vivo, the anti-proliferative effect for tumors was tested at two days post-subcutaneous cell inoculation.MUC-1 and uPA are strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts.Systemic injections of 111, 222 and 333 MBq/kg of alpha-conjugate caused significant tumor growth delay in a dose dependent manner after 16 weeks, compared with the non-specific control at 333 MBq/kg.

View Article: PubMed Central - PubMed

Affiliation: Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah, 2217, Australia. barry.allen@sesiahs.health.nsw.gov.au.

ABSTRACT
Evidence for the efficacy of targeted alpha therapy for the control of pancreatic cancer in preclinical models is reviewed. Results are given for in vitro pancreatic cancer cells and clusters and micro-metastatic cancer lesions in vivo. Two complementary targeting vectors are examined. These are the C595 monoclonal antibody that targets the MUC1 antigen and the PAI2 ligand that targets the uPA receptor. The expression of the tumor-associated antigen MUC-1 and the uPA receptor on three pancreatic cancer cell lines is reported for cell clusters, human mouse xenografts and lymph node metastases, as well as for human pancreatic cancer tissues, using immuno-histochemistry, confocal microscopy and flow cytometry. The targeting vectors C595 and PAI2 were labeled with the alpha emitting radioisotope 213Bi using the chelators cDTPA and CHX-A″ to form the alpha-conjugates (AC). Cell clusters were incubated with the AC and examined at 48 hours. Apoptosis was documented using the TUNEL assay. In vivo, the anti-proliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AC by local or systemic administration. Changes in tumor progression were assessed by tumor size. MUC-1 and uPA are strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The ACs can target pancreatic cells and regress cell clusters (~100 µm diameter), causing apoptosis in some 70-90 % of cells. At two days post-cell inoculation in mice, a single local injection of 74 MBq/kg of AC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of alpha-conjugate caused significant tumor growth delay in a dose dependent manner after 16 weeks, compared with the non-specific control at 333 MBq/kg. Cytotoxicity was assessed by the MTS and TUNEL assays. The C595 and PAI2-alpha conjugates are indicated for the treatment of micro-metastatic pancreatic cancer with over-expression of MUC1 and uPA receptors in post-surgical patients with minimal residual disease. The observation of tumor regression in a Phase I clinical trial of targeted alpha therapy for metastatic melanoma indicates that alpha therapy can regress tumors by a process called tumor anti-vascular alpha therapy (TAVAT). As a consequence, this therapy could be indicated for the management of non-surgical pancreatic cancer tumors.

No MeSH data available.


Related in: MedlinePlus

Dose effect of 213Bi-CHX-A″-C595 on body weight of mice over time [17].
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f6-cancers-03-01821: Dose effect of 213Bi-CHX-A″-C595 on body weight of mice over time [17].

Mentions: Change in mouse bodyweight with time is shown in Figure 6 for IP injections of 222, 296 and 370 MBq/kg of AIC, using the CHX-A″ chelator. Test mice suffered a small, short-term weight loss before embarking on a growth rate similar to that for the controls over ten weeks.


Targeted alpha therapy approach to the management of pancreatic cancer.

Allen BJ, Rizvi SM, Qu CF, Smith RC - Cancers (Basel) (2011)

Dose effect of 213Bi-CHX-A″-C595 on body weight of mice over time [17].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757392&req=5

f6-cancers-03-01821: Dose effect of 213Bi-CHX-A″-C595 on body weight of mice over time [17].
Mentions: Change in mouse bodyweight with time is shown in Figure 6 for IP injections of 222, 296 and 370 MBq/kg of AIC, using the CHX-A″ chelator. Test mice suffered a small, short-term weight loss before embarking on a growth rate similar to that for the controls over ten weeks.

Bottom Line: In vivo, the anti-proliferative effect for tumors was tested at two days post-subcutaneous cell inoculation.MUC-1 and uPA are strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts.Systemic injections of 111, 222 and 333 MBq/kg of alpha-conjugate caused significant tumor growth delay in a dose dependent manner after 16 weeks, compared with the non-specific control at 333 MBq/kg.

View Article: PubMed Central - PubMed

Affiliation: Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah, 2217, Australia. barry.allen@sesiahs.health.nsw.gov.au.

ABSTRACT
Evidence for the efficacy of targeted alpha therapy for the control of pancreatic cancer in preclinical models is reviewed. Results are given for in vitro pancreatic cancer cells and clusters and micro-metastatic cancer lesions in vivo. Two complementary targeting vectors are examined. These are the C595 monoclonal antibody that targets the MUC1 antigen and the PAI2 ligand that targets the uPA receptor. The expression of the tumor-associated antigen MUC-1 and the uPA receptor on three pancreatic cancer cell lines is reported for cell clusters, human mouse xenografts and lymph node metastases, as well as for human pancreatic cancer tissues, using immuno-histochemistry, confocal microscopy and flow cytometry. The targeting vectors C595 and PAI2 were labeled with the alpha emitting radioisotope 213Bi using the chelators cDTPA and CHX-A″ to form the alpha-conjugates (AC). Cell clusters were incubated with the AC and examined at 48 hours. Apoptosis was documented using the TUNEL assay. In vivo, the anti-proliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AC by local or systemic administration. Changes in tumor progression were assessed by tumor size. MUC-1 and uPA are strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The ACs can target pancreatic cells and regress cell clusters (~100 µm diameter), causing apoptosis in some 70-90 % of cells. At two days post-cell inoculation in mice, a single local injection of 74 MBq/kg of AC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of alpha-conjugate caused significant tumor growth delay in a dose dependent manner after 16 weeks, compared with the non-specific control at 333 MBq/kg. Cytotoxicity was assessed by the MTS and TUNEL assays. The C595 and PAI2-alpha conjugates are indicated for the treatment of micro-metastatic pancreatic cancer with over-expression of MUC1 and uPA receptors in post-surgical patients with minimal residual disease. The observation of tumor regression in a Phase I clinical trial of targeted alpha therapy for metastatic melanoma indicates that alpha therapy can regress tumors by a process called tumor anti-vascular alpha therapy (TAVAT). As a consequence, this therapy could be indicated for the management of non-surgical pancreatic cancer tumors.

No MeSH data available.


Related in: MedlinePlus