PEVIVA Products in Oncology

Lung, breast, prostate and colon carcinomas are the most frequent forms of human malignancies. These tumors all arise from simple epithelial cells and express the intermediate filament protein keratin 18 (K18, cytokeratin 18 or CK18). During apoptosis, K18 is cleaved by caspases at two sites (see figure below).
Macrophages recognize and engulph apoptotic cells. This does not necessarily occur in tumor tissue and caspase-cleaved K18 may therefore be released to the extracellular environment and into the blood (see pop-up figure). Apoptosis of other cell types such as lymphoid cells will not generate K18 cleavage products. Caspase-cleaved K18 is therefore an ideal biomarker for monitoring apoptosis of carcinoma cells using blood samples.
The M30 Apoptosense® ELISA assay specifically detects caspase-cleaved K18 (ccK18) released from apoptotic tumor cells. The M30 Apoptosense® ELISA assay is designed to be used together with the M65 EpiDeath® ELISA assay which measures total K18. Determination of the ratio between caspase-cleaved to total K18 released from dead cells offers a unique possibility to determine cell death mode (apoptosis or necrosis (Kramer et al., 2004), please also see note on M30/M65 ratios).

Monitoring cancer treatment using K18 serum markers

Most of the clinically used anticancer agents induce apoptosis. Apoptosis is also an attractive outcome of treatment with novel therapeutic drugs in oncology. The M30 Apoptosense® ELISA and M65® ELISA assays are unique tests for monitoring tumor cell death during cancer treatment. Effective cancer treatment induces increases in caspase-cleaved and/or total K18 in the circulation within 24-72 hours. (Kramer et al., 2004; Kramer et al., 2006). These increases in serum/plasma K18 are associated with clinical response to treatment (Hägg Olofsson et al., 2007).

From model to man

The M30 Apoptosense® ELISA and M65® ELISA assays detect human, but not mouse/rat, K18 (Olofsson et al., 2009). The detection of K18 in the blood of a mouse carrying a human tumor xenograft is therefore due to apoptosis of the human tumor cells.

Peviva biomarkers offer an integrated concept for oncology drug development. The biomarkers can be used for cell-based screening (the possibility to use 3-D culture models is of particular interest; see information on M30 CytoDeath™ ELISA), for animal models and for clinical studies.