Molecular Probes plans to synthesize and characterize a large number of long wavelength diagnostic and photosensitizing dyes. The dyes are predominantly cationic and most examples are selected from the oxazine and thiazine classes of dyes. Several oxazine and thiazine derivatives were shown to be very potent and selectively toxic photosensitizers during Phase I. The chemical structures of the dyes will be modified to increase their selective phototoxicity. Other long wavelength dyes will also be investigated. Several approaches will be examined to increase selective delivery and toxicity of these agents to the target carcinoma cell. Derivatives will be prepared that serve as substrates for enzymes that concentrate in tumors, contain DNA intercalating groups, or contain moieties with known antineoplastic activity. The new derivatives will be screened in vitro and in vivo in collaboration with Dr. Allan R. Oseroff. The most effective new dyes will be investigated to determine their pharmacokinetics and mechanisms. The information obtained from the biological studies will be used to refine the dye structures to identify sensitizers with greater tumor selectivity, higher accumulation in carcinoma cells, better retention and lower toxicities than currently available sensitizers, as well as fluorescent probes for the identification of neoplastic cells and tissues.