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Page 12 of 14 Anand et al. J Cancer Metastasis Treat 2019;5:6 I http://dx.doi.org/10.20517/2394-4722.2018.98

shown to exert its effects on PpIX levels in murine and human SCC tumors by upregulating the levels
of two rate-limiting enzymes of the heme pathway, coproporphyrinogen oxidase (upregulation) and
ferrochelatase (down regulation), in a way that favors accumulation of higher PpIX levels inside the tumor
[24]
cells’ mitochondria . The ultimate consequence of elevated PpIX levels following CPBN pretreatment,
is a significant increase in tumor cell death after PDT. This is due not only to higher PpIX concentrations
within individual cells, but also to a more homogeneous distribution of high PpIX throughout the tumor
[Figure 1C]. Following PDT, the loss of tumor cells through apoptosis was demonstrated via TUNEL and
hematoxylin and eosin staining; thus, apoptosis clearly contributes to better outcomes such as retardation of
tumor growth in the CPBN-PDT treatment group. Our data regarding inhibitory effects of the CPBN-PDT
regimen upon metastases are particularly exciting. Although our sample sizes were relatively small and the
data should be considered somewhat preliminary, the CPBN-PDT combination appears to be more effective
at preventing metastatic spread than either CPBN or PDT alone [Figures 4 and 5].

The clinical implication of this study is the possibility that a new combination approach might bring PDT
closer to the forefront of options available for management of BCA. Mainline treatment options available
for BCA today include RT, surgery, chemotherapy, biological therapy (targeted agents), and hormonal
therapy. As approaches to BCA disease management have evolved, the focus has shifted toward breast
preservation, placing less emphasis on surgical and ablative approaches. In this setting, PDT, represents a
promising treatment and management strategy for the following reasons: (1) Unlike RT, PDT does not cause
fibrosis and scarring; (2) PDT can be repeated many times since it targets mitochondria rather than DNA,
and thereby poses minimal risk for inducing mutations and secondary tumors; (3) PDT has already been
successfully tried as a means to control recurrent BCA, especially for recurrences on the chest wall (which
are extremely resistant to chemotherapy for unknown reasons). Thus, a recent clinical trial from China
used ALA-mediated PDT in combination with RT for BCA metastases of the chest wall, and showed that
the alternating use of PDT and RT improved the complete response rate, and reduced the time to clearance,
[19]
when compared to RT alone . Increased use of PDT as a tissue-sparing adjunct for RT, would reduce the
amount of radiation-induced fibrosis and vascular damage (scarring, ulceration, dermatitis) suffered by
BCA patients, thereby representing a meaningful advance in clinical oncology; (4) it might be possible to
boost the efficacy of PDT, by using neoadjuvantal CPBN, to the extent that CPBN-PDT becomes useful as a
monotherapy. At the very least, CPBN-enhanced PDT would be more effective as an RT-sparing approach
when used together with RT; (5) future clinical translation of a CPBN-PDT approach is likely to be relatively
®
easy, since CPBN (trade name Xeloda) is already a well-established, FDA-approved agent for the treatment
of metastatic BCA.

In conclusion, based on our previous work showing that a combination of 5-FU given prior to PDT, leads
to enhanced ALA-mediated PpIX levels and greater tumor cell death following PDT in several different
epithelial cancers, we hypothesized here that CPBN might be a useful alternative to 5-FU as a neoadjuvant
with PDT for BCA. Because 5-FU might be quite toxic at the high systemic levels required to modulate
PpIX levels in BCA tumor, we reasoned that CPBN, a precursor to 5-FU, might serve as a safer yet equally
effective alternative. In this study, we compared the responses of 4T1 tumors when treated with either
conventional ALA-PDT, or with ALA-PDT preceded by oral CPBN. Our results revealed the following
major findings: (1) CPBN-enhanced PDT can be used to significantly increase the accumulation of PpIX in
murine breast tumors, and therefore represents a non-toxic alternative to 5-FU; (2) the pretreatment of 4T1
tumors with CPBN causes increased differentiation and decreased proliferation; (3) CPBN-enhanced PDT
improves photodynamic killing of the breast tumor cells; (4) a combination regimen using CPBN and PDT
significantly reduces distant metastases in the 4T1 tumor model. In summary, this treatment combination
has the potential to be an effective therapy for BCA metastases, and potentially for other types of cancer.
A more extensive version of this preclinical study would be immensely exciting and provide an additional
rationale for designing a clinical trial based upon this concept.