cancer chemotherapy drug design are exploiting non-nucleic acid strategies. These new
directions include:
- Angiogenesis inhibitors
- Proteases
- Signal transduction inhibitors
- Hormonal manipulation
- Photodynamic therapy
- Immunotherapy
These new directions can be used in combination with traditional anti-nucleic acid
approaches.
7.8.5.1 Angiogenesis Inhibitors
One characteristic of cancerous tumors is their rapid rate of growth. This accelerated
growth rate requires that the tumor establish its own blood supply to fuel its growth
needs.Angiogenesis is the formation of new blood vessels; uncontrolled angiogenesis
is a driving factor in solid tumor growth. Angiogenesis inhibitors should therefore, in
principle, halt uncontrolled tumor growth. The search for angiogenesis inhibitors was
initiated by seeking “endogenous angiogenesis inhibitors” in human tissues that typi-
cally lack blood vessels, such as cartilage. It was subsequently discovered that peptides
(such as CDPGYIGSR–NH 2 ) based on the laminin structure inhibit solid tumor growth
via an anti-angiogenesis mechanism. Synthetic heparin substitutes, such as sulphated
cyclodextrins, achieve the same goal. The search for natural product and synthetic
angiogenesis inhibitors is now an active area of ongoing research.
7.8.5.2 Protease Inhibitors
Another characteristic of cancerous tumors is their capacity to infiltrate adjacent tissues
and to colonize secondary sites (metastasis). To exhibit these biological capabilities,
tumor cells degrade the extracellular matrix that surrounds them through a process that
is mediated by proteases. An abnormally regulated elaboration of proteases appears to
be a characteristic of malignant cell lines. The extracellular matrix is degraded by a
complex array of metalloproteinases, including collagenases and gelatinases, which are
themselves turned on by tumor-secreted cysteine proteases and serine proteases.
Compounds that inhibit cysteine proteases or serine proteases (e.g., nafamostat,7.94)
are being evaluated as putative anticancer agents.
7.8.5.3 Kinase Inhibitors as Signal Transduction Inhibitors
To achieve rapid, uncontrolled growth with potential for metastasis, the tumor cell has
elaborate intracellular biosynthetic capabilities that enable it to fulfil its “vicious” growth
characteristics.Protein tyrosine kinasesare important to signal transduction in initiating
aberrant cellular transformation in malignant cells. Microbial products such as stau-
rosporine (7.95) have a demonstrated ability to inhibit kinases and may be a good start-
ing point for rational drug design. In addition to kinases, other cellular processes are
involved with signal transduction in cancerous cells and are thus targets for drug design.
ENDOGENOUS CELLULAR STRUCTURES 457