The structures of the u.v. chromophoric fragments of the antitumour antibiotics, PD 114,759 and PD 115,028

A complex of novel and exceptionally potent antibiotics has been evaluated for antitumor activity in vitro and in vivo and characterized with regard to their ability to cause DNA strand scission. The major component, PD 114,759, was quite active against all in vitro tumor systems including the human tumors, MCF-7 breast, HCT-8 colon, and A549 lung and the murine tumors M16/c mammary, Lewis lung, Pan 02 pancreas and L1210 leukemia. ID50 values ranged from 2-57 pg/ml. In vivo this agent produced significant increases of host life spans in mice bearing L1210 leukemia, B16 melanoma and the M5076 sarcoma. Further, it inhibited growth of subcutaneous implants of the Ridgway osteogenic sarcoma by 80% and growth of the MX-1 human mammary xenograft by 90-95%. PD 114,759, however, had no activity against the colon adenocarcinoma 11a or mammary adenocarcinoma 16c. Chinese hamster ovary cells exposed for 24 hours to concentrations of PD 114,759 ranging from 18 to 37 pg/ml accumulated in the S and G2+M phases of the cell cycle with a corresponding decrease in G1. Higher concentrations of drug apparently stopped any progression through the cell cycle. PD 114,759 caused significant DNA single strand breaks in L1210 cells exposed for 1 hour to drug concentrations as low as 20 pg/ml and the frequency of these lesions increased in proportion to the drug concentration. A portion of these DNA breaks appeared to be associated with protein. In contrast, no double strand DNA breaks were detected at the highest drug concentration tested (100 pg/ml).

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Potent antitumor antibiotic complex: PD 114,759, PD 115,028, PD 119,707, and PD 119,193.

Tunac¹,

Graham²,

Mamber³

et al. 1985

J. Antibiot.

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Four novel antitumor antibiotics (PD 114,759, PD 115,028, PD 119,707, and PD 119,193) are produced as a complex by a new species of Actinomadura.The proposed name for the culture is Actinomadura verrucosospora subsp. veractimyces ATCC 39363.The antibiotics are extremely bioactive, with MIC values of <0.006 ng/ml against several bacteria and ID50 values of 0.003~0.107 ng/ml against L1210 leukemia cells in vitro. Antitumor activities vs. P388 leukemia in vivo were observed at doses of 0.313, 0.40, and 0.5 t

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The structures of the u.v. chromophoric fragments of the antitumour antibiotics, PD 114,759 and PD 115,028

Cited by 6 publications

References 1 publication

The chemistry of DNA modification by antitumor antibiotics

The chemistry of DNA modification by antitumor antibiotics

Biological and biochemical activities of the novel antitumor antibiotic PD 114,759 and related derivatives

Potent antitumor antibiotic complex: PD 114,759, PD 115,028, PD 119,707, and PD 119,193.

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