86
D.C. Hill et al.
EL-4 cells. FR-111142 suppressed Meth A fibrosarcoma and solid colon tumour
growth in vivo in mice with no associated weight loss, but was not active against
leukaemia P388. The compound had low toxicity in vivo.
FR-111142 is closely related to the Aspergillusfumigatus metabolite fumagillin (Fig. 2) [48], which has also been reported to have antiangiogenic effects and
to have promising in vivo anti-tumour activities. Synthetic derivatives of FR1 11142 were prepared, and one of these, FR-118487, was found to have superior
properties and in vivo anti-tumour activity [49].
Other microbial metabolites discovered during screening programmes for
angiogenesis inhibitors include the pyridine derivatives WF-16775 AI and
A2 from Chaetasbolisia erysiophoides [50] and the anthracycline TAN-1120
(Fig. 2) from Streptomyces triangulatus sbsp. angiostaticus [51]. TAN-1120 is
reported to have particularly potent in vivo angiostatic activity.
2.4 CNS Disease
Cell-based assays involving growth and differentiation of neuroblastoma cell
lines have also been used successfully in the detection and isolation of novel
microbial metabolites.
2.4.1 Nerve Growth Factor ~GF) Mimics
Nerve growth factor is known to be important for the growth, survival and
functional maintenance of neurons in the central and peripheral nervous system.
Decrease in NGF availability has been implicated in various CNS disorders
such as Alzheimer's disease. NGF treatment has been shown to ameliorate
age-related impairment in memory tests.
A screening programme for NGF-like substances involved monitoring differentiation of the stable transformed mouse neuroblastoma cell line Neuro 2A.
Among the culture broths of 6000 soil isolates tested, only one culture, a Streptomyees sp., was found to cause generation of a neurite-like structure from the
Neuro 2A cell body. The metabolite responsible for this effect was purified and
identified as lactacystin, which has a novel thioester structure containing
y-lactam and N-acetylcysteine moieties [52, 53].
Further examination of the effects of lactacystin showed that the compound
induced formation of a microtubule-containing structure similar to that
observed in established neurites. Neurite formation in Neuro 2A cells may
be mediated by changes in intracellular cyclic AMP, protein kinase C and
cAMP-dependent protein kinase, and a proteinase inhibitor is known to have
a physiological role in neurite outgrowth. Lactacystin was assessed for activity
across these areas but had no effect on any of them apart from causing
a transient, dose-dependent increase in cAMP. This effect was coincident with
the formation of bipolar projections from the cells but did not take place at the
D.C. Hill et al.
EL-4 cells. FR-111142 suppressed Meth A fibrosarcoma and solid colon tumour
growth in vivo in mice with no associated weight loss, but was not active against
leukaemia P388. The compound had low toxicity in vivo.
FR-111142 is closely related to the Aspergillusfumigatus metabolite fumagillin (Fig. 2) [48], which has also been reported to have antiangiogenic effects and
to have promising in vivo anti-tumour activities. Synthetic derivatives of FR1 11142 were prepared, and one of these, FR-118487, was found to have superior
properties and in vivo anti-tumour activity [49].
Other microbial metabolites discovered during screening programmes for
angiogenesis inhibitors include the pyridine derivatives WF-16775 AI and
A2 from Chaetasbolisia erysiophoides [50] and the anthracycline TAN-1120
(Fig. 2) from Streptomyces triangulatus sbsp. angiostaticus [51]. TAN-1120 is
reported to have particularly potent in vivo angiostatic activity.
2.4 CNS Disease
Cell-based assays involving growth and differentiation of neuroblastoma cell
lines have also been used successfully in the detection and isolation of novel
microbial metabolites.
2.4.1 Nerve Growth Factor ~GF) Mimics
Nerve growth factor is known to be important for the growth, survival and
functional maintenance of neurons in the central and peripheral nervous system.
Decrease in NGF availability has been implicated in various CNS disorders
such as Alzheimer's disease. NGF treatment has been shown to ameliorate
age-related impairment in memory tests.
A screening programme for NGF-like substances involved monitoring differentiation of the stable transformed mouse neuroblastoma cell line Neuro 2A.
Among the culture broths of 6000 soil isolates tested, only one culture, a Streptomyees sp., was found to cause generation of a neurite-like structure from the
Neuro 2A cell body. The metabolite responsible for this effect was purified and
identified as lactacystin, which has a novel thioester structure containing
y-lactam and N-acetylcysteine moieties [52, 53].
Further examination of the effects of lactacystin showed that the compound
induced formation of a microtubule-containing structure similar to that
observed in established neurites. Neurite formation in Neuro 2A cells may
be mediated by changes in intracellular cyclic AMP, protein kinase C and
cAMP-dependent protein kinase, and a proteinase inhibitor is known to have
a physiological role in neurite outgrowth. Lactacystin was assessed for activity
across these areas but had no effect on any of them apart from causing
a transient, dose-dependent increase in cAMP. This effect was coincident with
the formation of bipolar projections from the cells but did not take place at the