cc-1065 and Neoplasms

In recent years, a series of new and highly cytotoxic analogues of CC-1065 and the duocarmycins have been developed that can be transformed into much less toxic prodrugs for the use in antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) and prodrug monotherapy (PMT) of cancer. In all these approaches, a relatively non-toxic prodrug is applied and subsequently converted selectively in the tumour tissue into a highly cytotoxic drug, thus reducing undesired side effects accompanying conventional chemotherapy. Here, the design and biological evaluation of prodrugs based on analogues of CC-1065 and the duocarmycins for the use in tumour selective cancer therapies is reviewed. The advantage of this approach is the excellent therapeutic index of some of the new prodrugs of over 5000 and the high cytotoxicity of the corresponding drugs with IC(50) values of as low as 16 pM (IC(50): concentration required for 50 % growth inhibition of target cells). In addition, a novel method for the correlation of the alkylation efficiency and the cytotoxicity based on mass spectrometry is described.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Duocarmycins; Humans; Indoles; Neoplasms; Prodrugs; Pyrrolidinones

The comparative DNA binding properties and cytotoxic activity of CDPIn methyl esters (n = 1-5) vs. PDE-In methyl esters (n = 1-3) are detailed in studies which provide experimental evidence for the intrinsic importance of stabilizing hydrophobic binding and non-covalent van der Waals contacts dominant in the CC-1065/B-DNA minor groove binding. High affinity minor groove binding to DNA was established through: (1) the observation of CDPI3 binding (UV) but not unwinding of supercoiled DNA (phi 174 RFI DNA) thus excluding intercalative binding; (2) the observation of CDPI3 binding to T4 phage DNA (UV, delta Tm) in which the major groove is occluded by glycosylation thus excluding major groove binding; (3) the observation of salt (Na+) concentration independent high affinity CDPI3 binding to poly(dA . poly(dT) thus excluding simple electrostatic binding to the DNA phosphate backbone; and further inferred through (4) the observation of an intense induced dichroism (ICD, poly(dA) . poly(dT) and poly(dG) . poly(dC) [phi]23(358) = 24,000 and 23,500). This high affinity minor groove binding is sufficient to produce a potent cytotoxic effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Antibiotics, Antineoplastic; Base Sequence; Carbamates; Chemical Phenomena; Chemistry, Physical; DNA; Duocarmycins; Humans; Indoles; Leucomycins; Macromolecular Substances; Molecular Conformation; Molecular Sequence Data; Molecular Structure; Neoplasms; Nucleic Acid Conformation; Pyrroles; Structure-Activity Relationship

The antibody-directed enzyme prodrug therapy allows a selective liberation of cytotoxic agents from non-toxic prodrugs in cancerous tissue by targeted antibody-enzyme conjugates. We have developed a series of novel glycosidic prodrugs based on the natural antibiotic CC-1065 and the duocarmycins, which are up to 4800 times less toxic than the drugs liberated from these prodrugs in the presence of the activating enzyme (e.g., beta-D-galactosidase). Furthermore, the drugs show very high cytotoxicities with IC(50) values of as low as 4.5 pm. In this report, we summarize our recent results on the development and biological evaluation of these novel third-generation prodrugs with higher water solubility, higher difference in cytotoxicity between the prodrugs and the corresponding drugs and improved cytotoxicity of the drugs as compared with previous compounds.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; beta-Galactosidase; Cell Line, Tumor; Drug Design; Duocarmycins; Glycosides; Humans; Indoles; Neoplasms; Prodrugs; Pyrroles; Stereoisomerism

An albumin-binding prodrug of the extremely potent CC-1065 analog, (+)-FDI-CBI, has been synthesized. This analog, (+)-FDI-CBIM, formed an albumin conjugate when added to human albumin in vitro. A greater amount (>3-fold) of the prodrug can be administered to animals compared to the free drug. The prodrug had significantly improved antitumor efficacy compared to the free drug in animal models using syngeneic animal tumors and human ovarian xenografted tumor cells. Antitumor drug delivery by in situ formation of drug-albumin conjugate is a promising strategy to improve antitumor efficacy.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Disease Models, Animal; Duocarmycins; Female; Humans; Indoles; Mice; Molecular Structure; Neoplasm Transplantation; Neoplasms; Prodrugs; Serum Albumin; Structure-Activity Relationship

Topics: Animals; Antineoplastic Agents; Apoptosis; Checkpoint Kinase 1; Drug Delivery Systems; Drug Screening Assays, Antitumor; Drugs, Investigational; Duocarmycins; Enzyme Inhibitors; Humans; Indoles; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Polyethylene Glycols; Protein Kinases; Receptor, IGF Type 1

Novel prodrugs of the cytotoxic antibiotic CC-1065 for an antibody-directed enzyme prodrug therapy (ADEPT) were prepared that show an excellent selectivity with a high toxicity of the corresponding drug. In particular, the seco-CBI analogue of CC-1065, 1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benz[e]indole, as well as the novel methyl-seco-CBI analogue 1-(1'-chloroethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole, were synthesized and transformed into their galactosides 10 a and 10 b, respectively. These galactosides can be cleaved with beta-D-galactosidase to give the free cytotoxic compounds. They were tested in in vitro cytotoxicity assays by using human bronchial carcinoma cells of line A549 in the presence and in the absence of beta-D-galactosidase. While the seco-CBI prodrugs revealed only modest selectivity, prodrugs of the methyl-seco-CBI analogue bearing an anti orientation of the substituents at the two stereogenic centers of the N-heterocycle displayed an excellent selectivity with an ED(50) quotient of about 750. The cytotoxicity of the corresponding phenol was rather high, with an ED(50) of 1.3 nM. The diastereomer with a syn orientation at the stereogenic centers was much less toxic.

Topics: Alkylation; Antibiotics, Antineoplastic; Antibodies; Antineoplastic Agents; Cell Division; DNA; Dose-Response Relationship, Drug; Drug Design; Duocarmycins; Enzyme Therapy; Glycosylation; Humans; Indoles; Leucomycins; Magnetic Resonance Spectroscopy; Mass Spectrometry; Neoplasms; Prodrugs; Substrate Specificity; Tumor Cells, Cultured

CC-1065 (NSC 298223) is the most cytotoxic agent tested against cells in culture in our laboratory. The 50% lethal doses for exponentially growing B16 melanoma and Chinese hamster ovary cells were 0.44 and 0.14 ng/ml, respectively, as compared to 35 and 500 ng/ml for Adriamycin. In the human tumor-cloning assay, 1-hr exposure to CC-1065 (0.1 ng/ml) caused greater than or equal to 50% lethality in a broad spectrum of tumors. The dose-survival curves for B16 and Chinese hamster ovary cells were characterized by an initial shoulder followed by an exponential decline with increasing dose. CC-1065 was more lethal to exponentially growing B16 cells (50% lethal dose = 0.44 ng/ml) than to plateau-phase cells (50% lethal dose = 1.2 ng/ml). CC-1065 inhibited DNA synthesis much more than did RNA or protein synthesis. After a 2-hr incubation with drug, inhibition of DNA synthesis was low immediately (0 hr) after drug exposure and reached maximum inhibition about 20 hr later. The doses for 50% inhibition of growth (0.18 ng/ml), survival (0.44 ng/ml), and DNA synthesis (0.15 ng/ml) were in the same range, whereas RNA synthesis was inhibited 50% at a much higher dose (5 ng/ml).

Topics: Animals; Antibiotics, Antineoplastic; Blood; Cell Division; Cell Line; Cell Survival; Cricetinae; Culture Media; DNA, Neoplasm; Duocarmycins; Female; Humans; Indoles; Kinetics; Leucomycins; Melanoma; Mice; Neoplasm Proteins; Neoplasms; Ovary; RNA, Neoplasm