The effects of hybrid cytotoxic
LH-RH analogs, produced by linking
anthraquinone or
methotrexate to carrier
LH-RH agonist [D-Lys6]
LH-RH, were evaluated in Copenhagen-Fisher F1 rats bearing Dunning R-3327H prostate
adenocarcinoma. The two cytotoxic
LH-RH analogs
T-98 [(D-Lys6)
LH-RH coupled to
glutaryl-2-(hydroxymethyl)anthraquinone (
G-HMAQ)], and AJ-04 [(D-Lys6)
LH-RH linked to
methotrexate (MTX)], carrier [D-Lys6]
LH-RH, or the free cytotoxic compounds MTX and
G-HMAQ were administered from Alzet Osmotic minipumps for 7-8 weeks. The cytotoxic
LH-RH analogs caused somewhat greater
tumor growth inhibition than the carrier
peptide, while
anthraquinone or
methotrexate alone, administered in equimolar doses, were ineffective. The inhibition of
androgen sensitive organs (testes, ventral prostates, and seminal vesicles) was pronounced with both carrier and cytotoxic analogs, showing the latter to be fully hormonally active in suppressing the pituitary-gonadal axis. Histological changes were also evaluated. The inhibition of mitosis and the frequency of apoptosis were higher in
tumors treated with AJ-04,
T-98, [D-Lys6]
LH-RH, or by
castration than in those of controls. Serum
hormone levels were lowered by both carrier
peptide and cytotoxic analogs, LH being substantially depressed, and
testosterone not detectable. These results and other findings indicate that
LH-RH analogs containing cytotoxic radicals
anthraquinone or
methotrexate retain their hormonal activity after administration in vivo, and can effectively inhibit
tumor growth. Extensive further studies are required on this new class of compounds, but apparent binding of cytotoxic
LH-RH analogs to
tumors such as
prostate cancer, which have receptors for
LH-RH, could greatly reduce peripheral toxicity of chemotherapeutic agents. This approach, based on targeted
chemotherapy, might be of practical therapeutic importance for the management of advanced
prostate cancers, which eventually relapse after palliative hormonal
therapy.