82
D.C. Hill et al.
target for development of therapeutic agents in inflammatory diseases and
cancer.
2.1.5 Other Screen Methodologies and Targets
A spectrophotometric assay for prevention of myeloperoxidase release from
polymorphonuclear leucocytes was used to discover the aseanostatins [28].
Inducers of the glycoprotein hormones known as colony stimulating factors
(CSF) which regulate blood cell formation and function have also been sought.
Leustroducsins A, B and C were discovered in one such programme using an
assay which monitored the effect of test samples on CSF production by KM-102
cells [29-31].
2.2 Cancer
Cellular physiology, proliferation and cell-cell interactions also play an important part in the establishment and development of cancer. Indeed several of the
targets for inflammatory disease and cancer overlap as described in the macrophage activation screening programme in Sect. 2.1.4.
2.2.1 Multidrug Resistance (MDR)
A major cause of failure of cancer chemotherapy is multidrug resistance, which
is the development of resistance to several structurally unrelated anticancer
agents. A specific glycoprotein, P-170, which apparently actively exports
cytotoxic compounds, is generally associated with multi-drug resistant (MDR)
cells. MDR modulators are therefore potentially important adjuncts to chemotherapeutic agents for the treatment of cancer.
From Aspergillus fiseheri vat. brasiliensis, 5-N-acetylardeemin was isolated
as an MDR modulator using assays on human tumour KB3-1 (normal) and
KBV-1 (multidrug resistant) cell lines [32, 33]. Compounds were tested against
KBV-1 cells and serially diluted vinblastine, in microtitre plates. After incubation, the cells were stained with methylene blue and assessed in comparison to
a control well containing no cytotoxic compound. Resistance and reversal were
calculated by comparing the concentration of the cytotoxic compound required
to reduce cells numbers to < 10% of the control well in each cell line. KBV-1
cells were 1600 times more resistant to vinblastine compared with KB3-1 cells.
In the presence of 10 gmol 1-1 5-N-acetylardeemin, however, KBV-1 cells were
significantly sensitised, with their comparative resistance to vinblastine being
reduced from 1600 to 6 times. Similarly, 5-N-acetylardeemin was shown to be
ten times more effective in chemosensitising KBV-1 cells than verapamil,
a known MDR modulator.
D.C. Hill et al.
target for development of therapeutic agents in inflammatory diseases and
cancer.
2.1.5 Other Screen Methodologies and Targets
A spectrophotometric assay for prevention of myeloperoxidase release from
polymorphonuclear leucocytes was used to discover the aseanostatins [28].
Inducers of the glycoprotein hormones known as colony stimulating factors
(CSF) which regulate blood cell formation and function have also been sought.
Leustroducsins A, B and C were discovered in one such programme using an
assay which monitored the effect of test samples on CSF production by KM-102
cells [29-31].
2.2 Cancer
Cellular physiology, proliferation and cell-cell interactions also play an important part in the establishment and development of cancer. Indeed several of the
targets for inflammatory disease and cancer overlap as described in the macrophage activation screening programme in Sect. 2.1.4.
2.2.1 Multidrug Resistance (MDR)
A major cause of failure of cancer chemotherapy is multidrug resistance, which
is the development of resistance to several structurally unrelated anticancer
agents. A specific glycoprotein, P-170, which apparently actively exports
cytotoxic compounds, is generally associated with multi-drug resistant (MDR)
cells. MDR modulators are therefore potentially important adjuncts to chemotherapeutic agents for the treatment of cancer.
From Aspergillus fiseheri vat. brasiliensis, 5-N-acetylardeemin was isolated
as an MDR modulator using assays on human tumour KB3-1 (normal) and
KBV-1 (multidrug resistant) cell lines [32, 33]. Compounds were tested against
KBV-1 cells and serially diluted vinblastine, in microtitre plates. After incubation, the cells were stained with methylene blue and assessed in comparison to
a control well containing no cytotoxic compound. Resistance and reversal were
calculated by comparing the concentration of the cytotoxic compound required
to reduce cells numbers to < 10% of the control well in each cell line. KBV-1
cells were 1600 times more resistant to vinblastine compared with KB3-1 cells.
In the presence of 10 gmol 1-1 5-N-acetylardeemin, however, KBV-1 cells were
significantly sensitised, with their comparative resistance to vinblastine being
reduced from 1600 to 6 times. Similarly, 5-N-acetylardeemin was shown to be
ten times more effective in chemosensitising KBV-1 cells than verapamil,
a known MDR modulator.