Breaking the Silence of Tumor Response: Future Prospects of Targeted Radionuclide Therapy.

Therapy-induced tumor resistance has always been a paramount hurdle in the clinical triumph of cancer therapy. Resistance acquired by tumor through interventions of chemotherapeutic drugs, ionizing radiation, and immunotherapy in the patients is a severe drawback and major cause of recurrence of tumor and failure of therapeutic responses. To counter acquired resistance in tumor cells, several strategies are practiced such as chemotherapy regimens, immunotherapy and immunoconjugates, but the outcome is very disappointing for the patients as well as clinicians. Radionuclide therapy using alpha or beta-emitting radionuclide as payload becoming a popular practice for cancer therapy. With the improvement in dosimetric studies, development of high-affinity target molecules and design of several novel chelating agents which provide thermodynamically stable complexes in vivo, the scope of radionuclide therapy has increased by leaps and bounds. Additionally, radionuclide therapy along with the combination of chemotherapy is gaining importance in pre-clinics, which is quite encouraging. Thus, it opens an avenue for newer cancer therapy modalities where chemotherapy, radiation therapy, and immunotherapy are unable to break the silence of tumor response. This article describes, in brief, the causes of tumor resistance and discusses the potential of radionuclide therapy to enhance tumor response.

Camptothecin enhances 131I-rituximab-induced G1-arrest and apoptosis in Burkitt lymphoma cells.

BACKGROUND: Rituximab is a chimeric monoclonal antibody against CD20. It is an established immunotherapeutic agent for non-Hodgkin's lymphoma. Even though rituximab has been used in clinics for decades, only 50% of the patients respond to rituximab therapy. To enhance the in vitro effect of rituximab, it was labeled with Iodine-131 (131I) and combined effect of 131I-rituximab and camptothecin (CPT) was studied on a tumor cell line expressing CD20. OBJECTIVE: The aim is to study the magnitude of cell killing and the underlying mechanism responsible for enhancing in vitro therapeutic efficacy. METHODS: Rituximab was labeled with 131I by the iodogen method. Raji cells were pretreated with CPT (250 nM) for an hour followed by 131I-rituximab (0.37 and 3.7 MBq) and incubated for 24 h in a humidified atmosphere of CO2 incubator at 37°C. Subsequently, Raji cells were harvested and thoroughly washed to carry out studies of cellular toxicity, apoptosis, cell cycle, and mitogen-activated protein kinase (MAPK) pathways. RESULTS: Maximal inhibition of cell proliferation and enhancement of apoptotic cell death was observed in the cells treated with the combination of CPT and 131I-rituximab, compared to controls of CPT-treated and 131I-rituximab-treated cells. Raji cells undergo G1 arrest after 131I-rituximab treatment, which leads to apoptosis and was confirmed by the downregulation of bclxl protein. Expression of p38 was decreased while an increase in phosphorylation of p38 was observed in the combination treatment of CPT and 131I-rituximab. CONCLUSIONS: It was concluded from the findings that CPT enhanced 131I-rituximab-induced apoptosis, G1 cell cycle arrest and p38 MAPK phosphorylation in Raji cells.