229ineffective treatment. Receiving ineffective therapy for longer than needed also delays
the start of second-line therapies that might work. Worse still, the failed treatment can
trigger genetic defense mechanisms in tumor cells that can make it resistant to second-
line therapies using other drugs. This phenomenon is known as cross-resistance.
The current months-long lag between the start of therapy and the appearance of
obvious signs of initial success or failure also affects how new therapies undergo
clinical testing. Because of the possibility of cross-resistance, FDA is reluctant to
allow testing of new cancer therapies on anyone but those patients who have
exhausted all other therapeutic possibilities. Unfortunately, such patients are far less
likely to respond to any therapy, making it far more diffi cult to prove the benefi ts of
an experimental therapy. This diffi culty is particularly true for the new generation of
molecularly targeted therapies that aim to stop tumor growth early in its progres-
sion. An available real-time apoptosis monitor might enable such drugs to be tested
at the initial diagnosis of cancer with less concern that prolonged therapy, should it
fail to work, would put patients at risk by letting their cancers grow unchecked for
longer than necessary. Instead, getting an early sign that such an early therapy is not
working would allow patients to receive conventional therapy more quickly.
Recognizing such a need, the NCI’s Unconventional Innovations Program is fund-
ing the development of an apoptosis detector.
Serum Nucleosomes as Indicators of Sensitivity
to Chemotherapy
In the nucleus of eukaryotic cells, DNA is associated with several protein compo-
nents and forms complexes known as nucleosomes. During cell death, particularly
during apoptosis, endonucleases are activated that cleave the chromatin into multi-
ple oligo- and mononucleosomes. Subsequently, these nucleosomes are packed into
apoptotic bodies and are engulfed by macrophages or neighboring cells. In cases of
high rates of cellular turnover and cell death, they also are released into the circula-
tion and can be detected in serum or plasma by Cell Death Detection-ELISAplus
(Roche Diagnostics). As enhanced cell death occurs under various pathologic con-
ditions, elevated amounts of circulating nucleosomes are not specifi c for any benign
or malignant disorder. However, the course of change in the nucleosomal levels in
circulation of patients with malignant tumors during chemotherapy or radiotherapy
is associated with the clinical outcome and can be useful for the therapeutic moni-
toring and the prediction of the therapeutic effi cacy.
In patients with inoperable small cell lung cancer, the effi cacy of chemotherapy
can be predicted early in the course of therapy by baseline values of serum nucleo-
somes as independent parameters. However, prediction of effi cacy of chemotherapy
in non-small cell lung cancer (NSCLC) requires consideration of the following:
- Staging
- Age