echinomycin and Neoplasms

Topics: Alkaloids; Animals; Antineoplastic Agents; Azacitidine; Biphenyl Compounds; Chrysenes; Deoxycytidine; Echinomycin; Epirubicin; Etanidazole; Flavonoids; Gemcitabine; Guanidines; Humans; Idarubicin; Menogaril; Mitoguazone; Neoplasms; Nitroimidazoles; Nogalamycin; Organoplatinum Compounds; Paclitaxel; Pentostatin; Polymers; Propylene Glycols; Ribavirin; Sulfonylurea Compounds; Trimetrexate; Vidarabine Phosphate

A combination of anti-CTLA-4 plus anti-PD-1/PD-L1 is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAEs). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrating myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFN-γ-dependent mechanism. Targeting the HIF-1α/PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated the cancer immunotherapeutic effects of anti-CTLA-4 therapy, with efficacy comparable to that of anti-CTLA-4 plus anti-PD-1 antibodies. However, while anti-PD-1 exacerbated irAEs triggered by ipilimumab, echinomycin protected mice against irAEs by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1/PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment to achieve safer and more effective immunotherapy.

Topics: Animals; B7-H1 Antigen; Echinomycin; Hypoxia-Inducible Factor 1, alpha Subunit; Immune Evasion; Immune Tolerance; Lymphocytes, Tumor-Infiltrating; Mice; Neoplasms; Tumor Microenvironment

Small-molecule compounds that target mismatched base pairs in DNA offer a novel prospective for cancer diagnosis and therapy. The potent anticancer antibiotic echinomycin functions by intercalating into DNA at CpG sites. Surprisingly, we found that the drug strongly prefers to bind to consecutive CpG steps separated by a single T:T mismatch. The preference appears to result from enhanced cooperativity associated with the binding of the second echinomycin molecule. Crystallographic studies reveal that this preference originates from the staggered quinoxaline rings of the two neighboring antibiotic molecules that surround the T:T mismatch forming continuous stacking interactions within the duplex. These and other associated changes in DNA conformation allow the formation of a minor groove pocket for tight binding of the second echinomycin molecule. We also show that echinomycin displays enhanced cytotoxicity against mismatch repair-deficient cell lines, raising the possibility of repurposing the drug for detection and treatment of mismatch repair-deficient cancers.

Topics: Antibiotics, Antineoplastic; Base Pair Mismatch; Cell Survival; Crystallography, X-Ray; DNA; Echinomycin; HCT116 Cells; Humans; Intercalating Agents; Molecular Structure; Neoplasms; Nucleic Acid Conformation

Two novel quinomycin derivatives, RK-1355A (1) and B (2), and one known quinomycin derivative, UK-63,598 (3), were isolated from a microbial metabolites fraction library of Streptomyces sp. RK88-1355 based on Natural Products Plot screening. The structural elucidation of 1 and 2 was established through two-dimensional NMR and mass spectrometric measurements. They belong to a class of quinomycin antibiotics family having 3-hydroxyquinaldic acid and a sulfoxide moiety. They are the first examples for natural products as a quinoline type quinomycin having a sulfoxide on the intramolecular cross-linkage. They showed potent antiproliferative activities against various cancer cell lines and they were also found to exhibit moderate antibacterial activity.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Discovery; Echinomycin; Escherichia coli; Humans; Inhibitory Concentration 50; Mice; Microbial Sensitivity Tests; Molecular Structure; Neoplasms; Small Molecule Libraries; Staphylococcus aureus; Streptomyces

Echinomycin was administered to 43 patients with advanced cancer in escalating doses ranging from 60 to 2128 mcg/m2. The dose-limiting toxicity of echinomycin administered as a 24-h continuous infusion every 28 days was nausea and vomiting beginning at the end of the 24 h infusion and lasting from 3 to 8 days. Other toxicities included sporadic thrombocytopenia and biochemical evidence of liver dysfunction characterized by elevations in SGOT. Peripheral vein phlebitis was noted in 100% of patients, and watery diarrhea of 24-48-h duration was noted in 7% of patients. The maximally tolerated dose of echinomycin was 2128 mcg/m2. The recommended dose for phase II trials utilizing the 24-h continuous infusion schedule is 1600 mcg/m2 repeated every 28 days with pretreatment antiemetics.

Topics: Adult; Aged; Drug Evaluation; Echinomycin; Female; Humans; Infusions, Intravenous; Liver Function Tests; Male; Middle Aged; Nausea; Neoplasms; Platelet Count; Quinoxalines; Thrombocytopenia; Vomiting

We have conducted a phase I study of the cyclic peptide echinomycin (Quinomycin A) on a schedule of administration of once every 4 weeks. Ten dose levels between 20 and 1800 micrograms/m2 were studied. Acute gastrointestinal toxicity, thrombocytopenia, and transient elevations of serum transaminases occurred at doses of greater than or equal to 1000 micrograms/m2. Gastrointestinal toxicity was severe and dose-limiting in several patients at doses of 1800 micrograms/m2. Thrombocytopenia was erratic, but generally increased with drug doses. Platelet count nadirs occurred 5-10 days after administration. Hepatic toxicity was reflected in transient elevations of serum transaminases without hyperbilirubinemia. Three patients experienced apparent anaphylactic reactions to doses of 1500 micrograms/m2. The maximum tolerated single dose of echinomycin was 1800 micrograms/m2. A starting phase II dose of 1500 micrograms/m2 is recommended.

Topics: Adult; Aged; Alanine Transaminase; Anaphylaxis; Aspartate Aminotransferases; Droperidol; Drug Administration Schedule; Drug Evaluation; Echinomycin; Female; Hematologic Diseases; Humans; Male; Middle Aged; Nausea; Neoplasms; Quinoxalines

A human tumor cloning system was utilized to screen for in vitro antitumor effects of the investigational anticancer agent Echinomycin. Tumors from 562 patients (24 different histological tumor types) were placed in culture. Two hundred fifty-five specimens were evaluable for drug sensitivity information (i.e., greater than or equal to 20 colonies in control plates). The overall in vitro response rates (defined as less than 50% survival of tumor colony-forming units) at three different doses of Echinomycin (0.001, 0.01, and 0.1 micrograms/ml) were between 16% and 19%. Echinomycin showed minor in vitro cytotoxic activity in breast and colon cancer, and in sarcoma. A comparison of these in vitro results with the results of phase-II clinical trials, as they become available, will help to evaluate the utility of the human tumor cloning system for predicting clinical antitumor activity of new antineoplastics.

Topics: Cell Survival; Cells, Cultured; Echinomycin; Female; Humans; Male; Neoplasms; Quinoxalines; Tumor Stem Cell Assay

The potential clinical activity of the new phase I drugs N-methylformamide (N-MF) and Echinomycin (ECH) was examined while still undergoing clinical toxicology trials by testing against fresh surgical explants of human tumors in the 6-day in vivo SRC Assay. Sixty-nine tumors representing different histologic types including breast, lung, colon, ovarian, and cervical, as well as neoplasms of undiagnosed origin, were screened against N-MF (NSC-3051) and ECH (NSC-526417) simultaneously with five standard chemotherapeutic agents used clinically for treatment of the specific type of cancer. Thus, activity of N-MF and ECH could be compared directly with that of standard agents tested in the same assay. Treatment schedule was QD1-5, and the criterion for drug activity was tumor graft regression greater than 20%. N-MF was active against 15/69 tumors with a response rate of 22%. ECH was also active against 15/69 tumors, yielding the same response rate. Although the response rates for N-MF and ECH were the same, indicating a similar degree of general anti-tumor activity as evaluated by the assay, N-MF showed greatest activity against lung tumors whereas ECH was more active against ovarian tumors. Twenty-six of 69 tumors (38%) were unresponsive to all drugs tested, only one tumor was responsive to both N-MF and ECH and no tumors were responsive to either N-MF or ECH alone. Cytoxan, one of the standard agents tested concurrently with both phase I drugs yielded a response rate of 35%, one and one-half times greater. Cervical and renal cancers and lymphomas were relatively unresponsive to both drugs.

Topics: Animals; Cyclophosphamide; Drug Evaluation; Echinomycin; Female; Formamides; Humans; Mice; Neoplasms; Quinoxalines; Transplantation, Heterologous