Cytotoxicity, radiosensitization, antitumor activity, and interaction with hyperthermia of a Co(III) mustard complex.
A complex of Co(III) with a nitro group and a bis(2-chloroethyl)amine moiety was prepared in an effort to develop a new anticancer agent with radiosensitizing capabilities, direct antitumor activity, and the ability to interact positively with clinically relevant hyperthermia temperatures. The activity of this drug was compared to a similar Co(III) complex, nitro-bis(2,4-pentanedionato)(pyridine)cobalt(III) [Co(Py)], which bears a pyridine moiety mustard of bis(2-chloroethyl)amine and should have no alkylating abilities. In EMT6 cells nitro-bis(2,4- pentanedionato)(bis(2-chloroethyl)amine)cobalt(III) [Co(BCA)] was significantly more cytotoxic than Co(Py) and both drugs were more toxic toward normally oxygenated than hypoxic cells. Hyperthermia (42 degrees C, 1 h) increased the slope of the concentration-dependent survival curve for Co(BCA) but not for Co(Py) in normally oxygenated EMT6 cells. Co(BCA) was an effective radiosensitizer of hypoxic EMT6 cells in vitro, producing a dose-modifying factor of 2.40. In the human squamous cell line SCC-25 and the nitrogen mustard-resistant subline SCC-25/HN2 Co(BCA) was more cytotoxic than Co(Py), and the lethality of Co(BCA) was only minimally diminished in the SCC-25/HN2 line. In mice bearing the L1210 leukemia i.p., Co(BCA) had a broad range of therapeutically effective dosage and produced a greater than 60-day increase in life span at a dose 20-fold less than was lethally toxic. In addition, in the FSaIIC murine fibrosarcoma, Co(BCA) produced a tumor growth delay of 9.4 days at 75 mg/kg i.p. daily x 5, but Co(Py) produced a delay of only 2.9 days at 50 mg/kg daily x 5 and was lethally toxic above this dose. These results indicate that Co(BCA) has significant antineoplastic effects in vitro and in vivo and interacts positively with both radiation and mild hyperthermia. Its broad therapeutic dose range further suggests potential clinical utility.
Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
B A
BA
Teicher
M J
MJ
Abrams
K W
KW
Rosbe
T S
TS
Herman
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000628:therapy; D002470:Cell Survival / Q000187:drug effects; D003035:Cobalt / Q000494:pharmacology; D003131:Combined Modality Therapy; D005354:Fibrosarcoma / Q000188:drug therapy / Q000628:therapy; D006801:Humans; D006979:Hyperthermia, Induced; D007939:Leukemia L1210 / Q000188:drug therapy / Q000628:therapy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000494:pharmacology; D010422:Pentanones / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D010422:Pentanones; D011838:Radiation-Sensitizing Agents; C066140:nitro-bis(2,4-pentanedionato)(bis(2-chloroethyl)amine)cobalt(III); C066139:nitro-bis(2,4-pentanedionato)(pyridine)cobalt(III); D003035:Cobalt