chromomycins and Colonic-Neoplasms

Differential cleavage at three restriction enzyme sites was used to determine the specific binding to DNA of the antitumour antibiotics mithramycin A (MTA), chromomycin A(3) (CRO) and six chromophore-modified analogues bearing shorter side chains attached at C-3, instead of the pentyl chain. All these antibiotics were obtained through combinatorial biosynthesis in the producer organisms. MTA, CRO and their six analogues showed differences in their capacity for inhibiting the rate of cleavage by restriction enzymes that recognize C/G-rich tracts. Changes in DNA melting temperature produced by these molecules were also analyzed, as well as their antiproliferative activities against a panel of colon, ovarian and prostate human carcinoma cell lines. Moreover, the cellular uptake of several analogues was examined to identify whether intracellular retention was related to cytotoxicity. These experimental approaches provided mutually consistent evidence of a seeming correlation between the strength of binding to DNA and the antiproliferative activity of the chromophore-modified molecules. Four of the analogues (mithramycin SK, mithramycin SDK, chromomycin SK and chromomycin SDK) showed promising biological profiles.

Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Chromomycin A3; Chromomycins; Colonic Neoplasms; Deoxyribonucleases, Type II Site-Specific; DNA Restriction Enzymes; Female; Flow Cytometry; Humans; Male; Ovarian Neoplasms; Plicamycin; Prostatic Neoplasms; Structure-Activity Relationship

Clinical effect of 5-fluorouracil or chromomycin-A3 alone, 5-fluorouracil + chromomycin-A3, and of the first two plus prednisolone on gastrointestinal and other solid tumors was evaluated. Out of 133 cases acceptable for evaluation, the number of responders was as follows: 3 (18.8%) of 6 cases treated with 5-fluorouracil alone, 1 (9.1%) of 11 cases treated with chromomycin-A3 or chromomycin-A3 hemisuccinate, 13 (21.7%) of 60 cases on the two-drug regimen, and 21 (45.7%) of 46 cases on the three-drug regimen. In cases of stomach carcinoma, response rate to the three-drug regimen was 54.2% (13/24), significantly higher than that of other regimens. At least 25% regression in the size of primary tumor was observed in 2 (7.1%) of 28 cases on the two-drug regimen and in 6 (33.3%) of 18 cases on the three-drug regimen. Of 51 cases on the three-drug regimen, steroid diabetes developed in 5 cases, moon face in 4 cases, and gastric ulcer in 1 case. However, toxic effect of these regimens (especially appearance of leucopenia) was less than those of previously tried combined regimens. The duration of response, on an average, was 10.8 weeks in 13 cases on the two-drug regimen and 11.7 weeks in 21 cases on the three-drug regimen. It was concluded from these results that a better response is obtained by the three-drug regimen than other regimens, and that prednisolone in combination, in addition to its favorable effect in improving the general condition of the patients, might enhance the anticancer effect of the drugs used in combination.

Topics: Adenocarcinoma; Breast Neoplasms; Chromomycins; Colonic Neoplasms; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Middle Aged; Prednisolone; Stomach Neoplasms

Chromomycin A3 was given to 43 patients with metastatic cancer in order to determine the tolerable dose when the drug was administered on an every-other-day dose schedule for a total of five iv push injections, with the course of therapy being repeated every 4 weeks. At least three patients were entered at each dose level, graduated in 0.1-mg/m2 increments between 0.7 and 1.6 mg/m2. The most common (19 patients) side effect was nausea and/or vomiting, but this was usually mild, lasted for a few hours, and diminished in severity with repeated injections. Skin necrosis due to drug extravasation was a problem early in the study, but was eliminated by injecting the drug through iv tubing. Transient elevations in SGOT and alkaline phosphatase levels were observed, but proved not to be of serious consequence. Renal toxicity proved to be the limiting factor in therapy. However, a dose level of 1.3 mg/m2 was found to be a tolerable level of drug administration in previously untreated patients. Objective tumor responses were noted in four patients (Hodgkin's disease, embryonal rhabdomyosarcoma, adenocarcinoma of the lung, and malignant melanoma).

Topics: Adenocarcinoma; Breast Neoplasms; Carcinoma, Squamous Cell; Chromomycins; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hodgkin Disease; Humans; Kidney Neoplasms; Lung Neoplasms; Lymphoma; Mandibular Neoplasms; Neoplasms; Pharyngeal Neoplasms; Stomach Neoplasms; Uterine Neoplasms