ra-vii and Neoplasms

Natural cyclopeptides are hot spots in chemical and pharmaceutical fields because of the wide spreading bio-resources, complex molecular structures and various bioactivities. Bio-producers of cyclopeptides distribute over almost every kingdom from bacteria to plants and animals. Many cyclopeptides contain non-coded amino acids and non-pepditic bonds. Most exciting characteristic of cyclopeptides is a range of interesting bioactivities such as antibiotics gramicidin-S (2), vancomycin (3) and daptomycin (4), immunosuppressive cyclosporin-A (1) and astin-C (8), and anti-tumor aplidine (5), RA-V (6) and RA-VII (7). Compounds 1-4 are being used in clinics; compounds 5-8 are in the stages of clinical trial or as a candidate for drug research. In this review, the progress in chemical and bioactive studies on these important natural bioactive cyclopeptides 1-8 are introduced, mainly including discovery, bioactivity, mechanism, QSAR and synthesis.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cyclosporine; Daptomycin; Depsipeptides; Gramicidin; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Molecular Structure; Neoplasms; Peptides, Cyclic; Quantitative Structure-Activity Relationship; Vancomycin

An antitumor substance, RA-700, isolated from Rubia akane or Rubia cordifolia has the novel structure. Phase I clinical study was conducted by the RA-700 clinical study group consisting of 6 institutions. A single dose administration and 5-day schedule administration were evaluated with 14 patients respectively. RA-700 was given from 0.2 to 1.4 mg/m2 in single i.v. dose study, from 0.4 to 2.0 mg/m2 in 5-day i.v. schedule study. Nausea and vomiting, fever, stomachache, mild hypotension and slight abnormality of electric-cardiogram were observed as the toxicities. In pharmacokinetic study, the elimination half-lives (t1/2) of RA-700 in plasma were 55 min, of alpha-phase and 3.9 hrs. of beta-phase by single dose study, and 23-25 min. of alpha-phase and 6-14 hrs. of beta-phase by 5-day schedule study. Accumulation was not found by 5-day schedule administration, and metabolite were not observed in plasma and urine. It seems that RA-700 is metabolized by the liver and excreted in the feces. In conclusion, the maximum tolerated dose was 1.4 mg/m2 for 5-day schedule administration.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Male; Middle Aged; Nausea; Neoplasms; Peptides, Cyclic

In vitro phase II study of a new cyclic hexapeptide anticancer agent, RA-700 was studied on the human tumor clonogenic assay. From the results of the study using the human tumor cell line of lung cancer (PC-6), RA-700 appears to possess time-dependent antitumor activity. Therefore, against the 148 human specimens of various malignancies, the chemosensitivity of RA-700 was tested at the concentrations of 10 micrograms/ml, 1 microgram/ml and 0.1 microgram/ml in continuous exposure schedule for 2 weeks by using the human tumor clonogenic assay. If the criteria for in vitro sensitivity was based on greater than or equal to 70% inhibition of colony formation, out of 148 specimens 59 specimens (40%) were evaluable and the chemosensitivity rate of RA-700 were 67% (4/6), 22% (2/9), 17% (3/18) and 10% (1/10) for ovarian cancer, non-small cell lung cancer, breast cancer and colorectal cancer, respectively. An overall chemosensitivity rate against 13 different histologic types of cancers was 22% (13/59) (greater than or equal to 70% inhibition of colony formation) and 39% (23/59) (greater than or equal to 50% inhibition of colony formation). RA-700 showed almost same chemosensitivity compared to that of five standard anticancer drugs (adriamycin, mitomycin C, cisplatin, vinblastine and 5-FU), but the spectrum of RA-700 activity appears to be different from that of the standard drugs. Furthermore, the antitumor activity of RA-700 had no relationship with prior chemotherapy. These results indicated that RA-700 is a candidate for phase I study.

Topics: Antineoplastic Agents, Phytogenic; Colony-Forming Units Assay; Drug Evaluation; Humans; Neoplasms; Peptides, Cyclic; Plant Extracts; Tumor Stem Cell Assay