In view of non-specific toxicity of most chemotherapeutic agents against normal cells, the development of targeted
chemotherapy is warranted. Efficient targeting of chemotherapeutic drugs to the cancerous area could be of great benefit for patients with advanced or metastatic
tumors. Targeted cytotoxic
peptide conjugates are hybrid molecules composed of a
peptide carrier which binds to receptors on
tumors and a cytotoxic moiety. New cytotoxic analogs of
LHRH,
AN-152 in which
doxorubicin (DOX) is linked to [d-Lys(6)]
LHRH, and
AN-207 which consists of
2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity binding and are much less toxic and more effective in vivo than their respective radicals in inhibiting
tumor growth in
LHRH receptor-positive models of human ovarian, mammary, or
prostatic cancer. These results suggest that targeted cytotoxic
LHRH analogs such as
AN-207 could be considered for treatment of these
cancers. The presence of receptors for
bombesin-like
peptides on a wide variety of
tumors prompted us to use some of our
bombesin/
gastrin-releasing peptide antagonists as carrier molecules. Cytotoxic
bombesin analogs, such as
AN-215 containing
AN-201, might find application in the treatment of
small cell lung carcinoma (SCLC), and colorectal, gastric, pancreatic, mammary, and
prostatic cancers. Since
somatostatin receptors are found in various human
neoplasms and the receptor subtypes to which octapeptide analogs bind with high affinity have been identified, we synthesized several cytotoxic
somatostatin analogs including AN-162 and
AN-238 containing DOX and
2-pyrrolino-DOX respectively, linked to octapeptide
RC-121. Cytotoxic
somatostatin analog
AN-238 efficaciously inhibits growth of human breast or
prostate cancers expressing
somatostatin receptors-2 and -5 and can be used for receptor-targeted
chemotherapy. Cytotoxic
somatostatin analogs might also find applications for the
therapy of human pancreatic, colorectal, and
gastric cancer as well as
brain tumors and non-SCLC. Cytotoxic compounds linked to analogs of hormonal
peptides like
LHRH,
bombesin, and
somatostatin that can be targeted to certain
tumors possessing receptors for those
peptides could be an important addition to oncological armamentarium.