AN IN-VIVO QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP FOR A CONGENERIC SERIES OF PYROPHEOPHORBIDE DERIVATIVES AS PHOTOSENSITIZERS FOR PHOTODYNAMIC THERAPY
Bw. Henderson et al., AN IN-VIVO QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP FOR A CONGENERIC SERIES OF PYROPHEOPHORBIDE DERIVATIVES AS PHOTOSENSITIZERS FOR PHOTODYNAMIC THERAPY, Cancer research, 57(18), 1997, pp. 4000-4007
An in vivo quantitative structure-activity relationship (QSAR) study w
as carried out on a congeneric series of pyropheophorbide photosensiti
zers to identify structural features critical for their antitumor acti
vity in photodynamic therapy (PDT). The structural elements evaluated
in this study include the length and shape (alkyl, alkenyl, cyclic, an
d secondary analogs) of the ether side chain. C3H mice, harboring the
radiation-induced fibrosarcoma tumor model, were used to study three b
iological response endpoints: tumor growth delay, tumor cell lethality
, and vascular perfusion. All three endpoints revealed highly similar
QSAR patterns that constituted a function of the alkyl ether chain len
gth and drug lipophilicity, which is defined as the log of the octanol
:water partition coefficient (log P). When the illumination of tumor,
tumor cells, or cutaneous vasculature occurred 24 h after sensitizer a
dministration, activities were minimal with analogs of log P less than
or equal to 5, increased dramatically between log P of 5-6, and peake
d between log P of 5.6-6.6. Activities declined gradually with higher
log P. The lack of activity of the least-lipophilic analogs was explai
ned in large part by their poor biodistribution characteristics, which
yielded negligible tumor and plasma drug levels at the time of treatm
ent with light. The progressively lower potencies of the most lipophil
ic analogs cannot be explained through the overall tumor and plasma ph
armacokinetics of photosensitizer because tumor and plasma concentrati
ons progressively increased with lipophilicity. When compensated for d
ifferences in tumor photosensitizer concentration, the 1-hexyl derivat
ive (optimal lipophilicity) was 5-fold more potent than the 1-dodecyl
derivative (more lipophilic) and 3-fold more potent than the 1-pentyl
analog (less lipophilic), indicating that, in addition to the overall
tumor pharmacokinetics, pharmacodynamic factors may influence PDT acti
vity. Drug lipophilicity was highly predictive for photodynamic activi
ty. QSAR modeling revealed that direct antitumor effects and vascular
PDT effects may be governed by common mechanisms, and that the mere as
sociation of high levels of photosensitizer in the tumor tissue is not
sufficient for optimal PDT efficiency.