92
S. B. Christensen et al.
In antibody-drug conjugates, the payload is conjugated with an antibody via a
linker. The prodrug is administered to a patient and after binding to the cancer cell
surface, the prodrug is internalized by the cell and the cytotoxin released. Three
ADC’s, gemtuzumab ozogamicin, brentuximab vedotin and inotuzumab ozogamicin
have been approved to treat hematologic cancers and trastuzumab emtansine has been
approved for the treatment of breast cancer [165, 166]. Even though these drugs show
beneficial effects, the toxicity profiles of these are comparable to those of other cancer
chemotherapeutics, meaning that the expected selectivity is not obtained. In spite of
these problems, a number of other ADCs are under development (Fig. 14) [167].
12.2 Targeting of Thapsigargin
In the case of thapsigargin (1), selective activation of prodrug forms was attempted
by taking advantage of enzymes with particular specificity present in tumors: human
kallikrein-related peptidase 2 (KLK2, former human kallikrein 2 or hK2) and
prostate-specific antigen (PSA), also known as human kallikrein-related peptidase
3 [168]. Later, prostate-specific membrane antigen (PSMA) was added as a tool for
targeting 1 [94].
Prostate cancer cells, like normal prostate epithelial cells, express and secrete
PSA. The serine protease PSA belongs to the human kallikrein protease family [169,
170]. In the fluids of the gland, PSA cleaves semenogelins that mediate gel formation
in the semen. After diffusion into the circulation, the majority of PSA is inactivated
either by cleavage or by complexation with proteins [169]. The increased level of
PSA, because of production in prostate cancer tumors as well as in the prostate gland,
is used as a marker for prostate cancer [169, 170]. The observation that PSA is only
active in the vicinity of prostate cancer tumors, besides the prostate gland, has led
to the idea that conjugation of a cytotoxin like doxorubicin to a peptide cleaved by
PSA via a linker might afford a prodrug that is only cleaved in the vicinity of prostate
cancer cells and consequently is targeted towards prostate cancer tumors (Fig. 15)
[171, 172]. A drawback with doxorubicin is that the compound is a topoisomerase
II inhibitor and consequently most active when the cells are in a highly proliferative
state [173].
Kallikrein-related peptidase 2 is also secreted from both the prostate and prostate
cancer cells [174, 175]. Like PSA, the blood level of this enzyme might be used as
a marker for prostate cancer, and like PSA, KLK2 is inactivated after entering the
blood [176].
Prostate-specific membrane antigen (PSMA) is a putative class II transmembranous glycoprotein. It efficiently cleaves poly-γ-glutamyl sequences [177].
The active site of the enzyme is located on the outside of the cell enabling it to cleave
prodrugs in the vascular tissue (Fig. 16). The enzyme is found in the prostate gland
and is highly expressed in the neovascular tissue of a number of tumors, including
S. B. Christensen et al.
In antibody-drug conjugates, the payload is conjugated with an antibody via a
linker. The prodrug is administered to a patient and after binding to the cancer cell
surface, the prodrug is internalized by the cell and the cytotoxin released. Three
ADC’s, gemtuzumab ozogamicin, brentuximab vedotin and inotuzumab ozogamicin
have been approved to treat hematologic cancers and trastuzumab emtansine has been
approved for the treatment of breast cancer [165, 166]. Even though these drugs show
beneficial effects, the toxicity profiles of these are comparable to those of other cancer
chemotherapeutics, meaning that the expected selectivity is not obtained. In spite of
these problems, a number of other ADCs are under development (Fig. 14) [167].
12.2 Targeting of Thapsigargin
In the case of thapsigargin (1), selective activation of prodrug forms was attempted
by taking advantage of enzymes with particular specificity present in tumors: human
kallikrein-related peptidase 2 (KLK2, former human kallikrein 2 or hK2) and
prostate-specific antigen (PSA), also known as human kallikrein-related peptidase
3 [168]. Later, prostate-specific membrane antigen (PSMA) was added as a tool for
targeting 1 [94].
Prostate cancer cells, like normal prostate epithelial cells, express and secrete
PSA. The serine protease PSA belongs to the human kallikrein protease family [169,
170]. In the fluids of the gland, PSA cleaves semenogelins that mediate gel formation
in the semen. After diffusion into the circulation, the majority of PSA is inactivated
either by cleavage or by complexation with proteins [169]. The increased level of
PSA, because of production in prostate cancer tumors as well as in the prostate gland,
is used as a marker for prostate cancer [169, 170]. The observation that PSA is only
active in the vicinity of prostate cancer tumors, besides the prostate gland, has led
to the idea that conjugation of a cytotoxin like doxorubicin to a peptide cleaved by
PSA via a linker might afford a prodrug that is only cleaved in the vicinity of prostate
cancer cells and consequently is targeted towards prostate cancer tumors (Fig. 15)
[171, 172]. A drawback with doxorubicin is that the compound is a topoisomerase
II inhibitor and consequently most active when the cells are in a highly proliferative
state [173].
Kallikrein-related peptidase 2 is also secreted from both the prostate and prostate
cancer cells [174, 175]. Like PSA, the blood level of this enzyme might be used as
a marker for prostate cancer, and like PSA, KLK2 is inactivated after entering the
blood [176].
Prostate-specific membrane antigen (PSMA) is a putative class II transmembranous glycoprotein. It efficiently cleaves poly-γ-glutamyl sequences [177].
The active site of the enzyme is located on the outside of the cell enabling it to cleave
prodrugs in the vascular tissue (Fig. 16). The enzyme is found in the prostate gland
and is highly expressed in the neovascular tissue of a number of tumors, including