Pattern of antitumor activity of a novel camptothecin, ST1481, in a large panel of human tumor xenografts.
OBJECTIVE
ST1481 is the lead compound of a novel series of 7-modified camptothecins, the 7-oxyimino methyl derivatives, characterized by potent topoisomerase I inhibition and cytotoxic activity. Based on its therapeutic efficacy in a human non-small cell lung carcinoma model and its favorable pharmacological profile, the novel analogue was selected for further preclinical development.


METHODS
We investigated the growth-inhibitory effects of ST1481 and topotecan, used as a reference compound, in a panel of human tumor cell lines of various tumor types (ovarian carcinoma, glioblastoma, osteosarcoma, and melanoma), including sublines with acquired resistance to cisplatin. We explored the antitumor efficacy in a large panel of human tumor xenografts, with particular reference to intrinsically resistant tumor types, using oral administration and an intermittent treatment schedule.


RESULTS
ST1481 showed a potent antiproliferative activity with comparable effects in all tested cell lines. Only U-87-MG glioma cells were less sensitive, presumably as a consequence of the efficiency of the S-phase checkpoint. ST1481 produced a remarkable antitumor effect (tumor volume inhibition > 85%) in 16 of 18 examined models, with an appreciable rate of complete tumor regressions in 11 of 18 models (despite the nonoptimal intermittent treatment schedule). The most impressive antitumor effects were observed against lung carcinoma, melanoma, and osteosarcoma models, as documented by the high rate of complete responses (up to 100%). The efficacy of ST1481 was significantly superior to that of topotecan in 9 of 17 tumors. The novel drug was also markedly effective against slowly growing tumors (A549 lung carcinoma and HT29 colon carcinoma) when a daily protracted treatment was used to fully exploit the therapeutic potential of camptothecins.


CONCLUSIONS
The unusual potency of ST1481 in a variety of tumor cell lines suggests the ability of the drug to overcome several resistance factors. The profile of antitumor efficacy further supports the therapeutic interest in the novel analogue and provides a rational basis for clinical evaluation in selected tumor types.
Pratesi
Graziella
G
Istituto Nazionale Tumori, 20133 Milan, Italy. graziella.pratesi@istitutotumori.mi.it
De Cesare
Michelandrea
M
Carenini
Nives
N
Perego
Paola
P
Righetti
Sabina C
SC
Cucco
Carla
C
Merlini
Lucio
L
Pisano
Claudio
C
Penco
Sergio
S
Carminati
Paolo
P
Vesci
Loredana
L
Zunino
Franco
F
D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; C433984:ST 1481; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D002166:Camptothecin