cc-1065 and Lung-Neoplasms

Novel diastereomerically pure beta-D-galactosidic prodrugs (+)-12 a-e of the cytotoxic antibiotics CC-1065 and the duocarmycins were prepared for an antibody directed enzyme prodrug therapy (ADEPT) using 4 as a substrate via a radical cyclization to give rac-5 and rac-6 followed by a chromatographic resolution of the enantiomers of rac-5, glycosidation and linkage to the DNA-binding units 10 a-e. These only slightly toxic compounds can be toxified enzymatically by an antibody-beta-D-galactosidase conjugate at the surface of malignant cells to give the cytotoxic drugs, which then alkylate DNA. The new prodrugs were tested in in vitro cytotoxicity assays showing excellent QIC(50) values of 4800 and 4300 for (+)-12 a and (+)-12 b, respectively. The absolute configuration of precursor (+)-5 was determined by comparison of the experimental CD spectrum with the theoretically predicted CD spectra and by X-ray structure analysis.

Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Duocarmycins; Humans; Indoles; Inhibitory Concentration 50; Lung Neoplasms; Molecular Structure; Prodrugs; Pyrroles; Stereoisomerism

The in vivo genotoxic effects of the antitumor antibiotic, (+)-CC-1065, and its unnatural enantiomer, (-)-CC-1065, were investigated in two mouse models. These two compounds alkylate AT-rich regions of double stranded DNA with distinct sequence selectivities. (+)-CC-1065 dose-dependently increased the chromosomal aberration frequency in bone marrow cells of CD-1 mice from 1.2 +/- 0.8% in vehicle control animals to 5.0 +/- 1.2%, 11.4 +/- 3.9%, and 20.6 +/- 2.3% 24 hours following single intravenous doses of 2, 4, and 8 micrograms/kg, respectively. (-)-CC-1065 was significantly less potent with a maximal response at 8 micrograms/kg approximately one-third of that observed for (+)-CC-1065. (+)-CC-1065 induced a significant (P < or = 0.05), three-fold increase in the number of lung tumors/mouse in strain A/J mice from 0.27 +/- 0.15 for vehicle control animals to 0.83 +/- 0.15 24 weeks following a single intravenous dose of 8 micrograms/kg. This effect was paralleled by corresponding threefold increases in the percentage of mice with tumors and the percentage of mice with multiple tumors, compared to vehicle controls. (-)-CC-1065 at 8 micrograms/kg induced 0.67 +/- 0.15 tumors/mouse and resulted in slightly smaller increases in the tumor incidence and multiple tumor incidence, compared to (+)-CC-1065. The above results demonstrate that single intravenous doses of (+)- CC-1065 and (-)-CC-1065 which cause chromosomal damage in CD-1 mice also induce an increased incidence of lung tumors in A/J mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antibiotics, Antineoplastic; Bone Marrow; Carcinogenicity Tests; Chromosome Aberrations; Duocarmycins; Indoles; Leucomycins; Lung Neoplasms; Mice; Mice, Inbred A; Mutagens; Stereoisomerism

1,2-Dihydro-1-(chloromethyl)-5-hydroxy-8-methyl-3H-furano[3,2-e]in dole (CFI) as a novel replacement of the cyclopropylpyrroloindoline (CPI) alkylation subunit of CC-1065, U-71184, and U-73975 (adozelesin) has been synthesized and incorporated into a series of efficacious antineoplastic agents. A partial solution to an asymmetric synthesis of the CFI alkylation subunit has been achieved by the implementation of an asymmetric hydroboration reaction of an intermediate 3-methyleneindoline (13). Extension to the asymmetric synthesis of the CBI and CI alkylation subunits is presented. The demonstration and comparative study of the sequence-selective DNA alkylation properties of the CFI-based agents are detailed, and the preliminary in vitro and in vivo antineoplastic properties of these agents in the human epidermoid cell lung carcinoma (T222) are described.

Topics: Alkylation; Animals; Antineoplastic Agents; Base Sequence; Benzofurans; Boron Compounds; Carcinoma, Squamous Cell; Cyclohexanecarboxylic Acids; Cyclohexenes; DNA; Drug Screening Assays, Antitumor; Duocarmycins; Female; Furans; Humans; Indoles; Leucomycins; Lung Neoplasms; Mice; Mice, Nude; Molecular Sequence Data; Tumor Cells, Cultured

U-73,975 (U-73) and U-77,779 (U-77), two analogues of the cyclopropylpyrroloindole antitumor antibiotic CC-1065, are promising novel chemotherapeutic agents which are known to alkylate the N3 position of adenine in a sequence-selective manner. The concentration of U-73 required to produce a 1 log cell kill in 6 human tumor cell lines varied from 20-60 pM. U-77 was more cytotoxic than U-73, with the concentrations required for a 1 log cell kill ranging from 1-20 pM. The cytotoxicity of U-73 and U-77 was found to be independent of the guanine O6-alkyltransferase phenotype. The sensitivity of the BE and HT-29 human colon carcinoma cells was increased when the time of drug exposure was increased from 2 to 6 h. DNA interstrand cross-links, as measured by the technique of alkaline elution, could only be detected when HT-29 or BE cells were exposed to extremely high concentrations of U-77 for 6 h. No other forms of DNA damage were detected in genomic DNA with either compound. U-77 was also found to induce DNA interstrand cross-links in naked DNA, as measured by an agarose gel method. The rate of interstrand cross-linking was extremely rapid with the "second-arm" of the cross-link being completed within 2 h. The mechanism by which these cyclopropylpyrroloindole compounds elicit their cytotoxicity, however, remains to be elucidated.

Topics: Antibiotics, Antineoplastic; Benzofurans; Carcinoma; Cell Death; Colonic Neoplasms; Cross-Linking Reagents; Cyclohexanecarboxylic Acids; Cyclohexenes; DNA Damage; Dose-Response Relationship, Drug; Duocarmycins; Humans; Indoles; Leucomycins; Lung Neoplasms; Plasmids; Tumor Cells, Cultured; Urea