Doxorubicin bound to a HPMA copolymer carrier through hydrazone bond is effective also in a cancer cell line with a limited content of lysosomes.
We have synthesized conjugates containing doxorubicin (DOX) bound to oligopeptide side chains (GlyGly or GlyPheLeuGly) of a water-soluble copolymer carrier based on poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) either through proteolytically (PK1 conjugates) [Synthetic polymeric drugs. U.S. Patent 5,037,883 (1991)] or hydrolytically cleavable bond (HC conjugates). Pharmacological efficacy of PK1 and HC conjugates was compared in vitro on murine: T-cell lymphoma EL4, B-cell leukemia BCL1, B-cell lymphoma 38C13, leukemia P388 and Con A-stimulated A/Ph splenocytes and on human: primary (SW480) and metastatic (SW620) colorectal cancer cell lines parent and transfected with Thy 1.2 gene [2] and on erythromyeloid leukemia cell line K 562. Inhibition of proliferation determined by 3[H]-thymidine incorporation revealed that the cytostatic effect of HC conjugates is up to two orders of magnitude higher compared to PK1 conjugates. In some cancer cell lines (SW 620/T, SW 480) the pharmacological activity of HC conjugates is in vitro comparable with the activity of the free drug. Unlike PK1 conjugates, HC conjugates with a lysosomally degradable spacer (GlyPheLeuGly) are less effective compared to HC conjugates containing lysosomally non-degradable spacer (GlyGly). Moreover, HC conjugates exert pronounced anti-proliferative activity also in erythroblastoid leukemia cell line K 562 with a limited content of lysosomes.
Ríhová
B
B
Institute of Microbiology, Academy of Sciences of the Czech Republic, 14220 Prague 4, Czech Republic. rihova@biomed.cas.cz
Etrych
T
T
Pechar
M
M
Jelínková
M
M
Stastný
M
M
Hovorka
O
O
Kovár
M
M
Ulbrich
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D004337:Drug Carriers; D006835:Hydrazones / Q000737:chemistry*; D008247:Lysosomes / Q000737:chemistry*; D008689:Methacrylates; D051379:Mice; D008970:Molecular Weight; D009369:Neoplasms / Q000188:drug therapy*; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry; D011109:Polymethacrylic Acids; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D006835:Hydrazones; D008689:Methacrylates; D009842:Oligopeptides; D011109:Polymethacrylic Acids; C011533:Duxon; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate