Lonidamine as a modulator of alkylating agent activity in vitro and in vivo.
We are searching for relatively nontoxic compounds that can positively modulate the efficacy of antitumor alkylating agents. Lonidamine inhibits cellular energy metabolism and could potentially increase damage by alkylating agents if cellular defenses are energy requiring. Exposure of cells to lonidamine (500 microM) for 2 h under hypoxic conditions followed by 1-h exposures to lonidamine plus alkylating agents under normally oxygenated conditions in vitro significantly increased the cell kill achieved by cis-diamminedichloroplatinum(II) (CDDP) approximately 5-fold and by D-tetraplatin approximately 10-fold at 90% inhibitory concentration in MCF-7/CDDP (CDDP-resistant) cells. Carboplatin cytotoxicity, however, was little changed. In the MCF-7 parent cell line, treatment with lonidamine increased CDDP cytotoxicity by approximately 10-fold, D-tetraplatin by approximately 10-fold, and carboplatin by approximately 8-fold at the 90% inhibitory concentration. For L-phenylalanine mustard (melphalan), N,N',N"-triethylenethiophosphoramide (thiotepa), and N,N'-bis(2-chloroethyl)-N-nitrosourea, little resistance was evident in the MCF-7/CDDP lines compared with the parent line. Treatment with lonidamine increased the cytotoxicity of each drug by 1.5- to 3-fold in both cell lines. When exposure to lonidamine was extended to 24 h before and 12 h after drug exposure in MCF-7 normally oxygenated cultures, CDDP (250 microM) cytotoxicity was increased by approximately 100-fold, but melphalan cytotoxicity was increased only 2- to 3-fold over the concentration range tested. In the FSaIIC murine fibrosarcoma tumor system, five i.p. injections of 50 mg/kg of lonidamine over 36 h increased the tumor cell kill by CDDP and carboplatin approximately 2- to 3-fold over the dose range tested when the platinum complexes were given i.p. immediately after the third lonidamine injection. When cyclophosphamide and thiotepa were given in the same schedule, 10-fold increases in tumor cell killing were evident on tumor excision assay over the dosage ranges. The increase in bone marrow toxicity caused by lonidamine in addition to the alkylating agents was less than for tumor cells. Finally, in the EMT6 murine mammary carcinoma, use of lonidamine at 500 mg/kg twice daily along with CDDP, carboplatin, thiotepa, and cyclophosphamide significantly increased tumor growth delays by approximately 1.6- to 3.0-fold. The results suggest that lonidamine can positively modulate antitumor alkylating agent cytotoxicity and may be a clinically useful adjunctive therapy with these drugs.
Teicher
B A
BA
Dana-Farber Cancer Institute, Boston, Massachusetts.
Herman
T S
TS
Holden
S A
SA
Epelbaum
R
R
Liu
S D
SD
Frei
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D016190:Carboplatin / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005354:Fibrosarcoma / Q000188:drug therapy*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy*; D051379:Mice; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D007191:Indazoles; D009944:Organoplatinum Compounds; C055423:didimethylsulfoxide dichloroplatinum(II); D016190:Carboplatin; D002330:Carmustine; C016371:lonidamine