FCE 24157 (chemically (beta-[1-methyl-4-(1-methyl-4--[1-methyl-4-(4-N,N- bis(2-chloroethyl) amino-benzene-1-carboxy-amido) pyrrole-2-carboxiamido]pyrrole-2-carboxyamido)pyrrole-2-c arboxyamido]) propionamidine, hydrochloride) is a distamycin A (Dista A) derivative bearing a benzoyl mustard moiety instead of the formyl group at the N-terminal. Contrary to Dista A, FCE 24517 has been found to display potent cytotoxic activity on human and murine tumour cell lines. The compound maintains activity on melphalan (L-PAM)-resistant cells, whereas cross-resistance is observed on doxorubicin-(DX)-resistant cells. In vivo, FCE 24517 was found to possess evident antineoplastic activity on a series of murine transplanted solid tumours and human tumour xenografts. The following neoplasms were in fact found to be sensitive to FCE 24517 treatment: M14 human melanoma xenograft, N592 human small cell lung carcinoma, MTV murine mammary carcinoma, Colon 38 murine carcinoma, PO2 murine pancreatic carcinoma and M5076 murine reticulosarcoma. Lower effectiveness was observed against the murine P388 and Gross leukaemia, Lewis lung murine carcinoma, LoVo human colon carcinoma xenografts and A459 human lung adenocarcinoma. Against the murine L1210 leukaemia, FCE 24517 displayed a clear activity only when the tumour was transplanted i.p. and treatment was given i.p., whereas only marginal activity was seen against this leukaemia if transplanted i.v. and the drug was given i.v. As true also in vitro, FCE 24517 was effective against i.p. implanted L1210 leukaemia resistant to L-PAM. The mode(s) of action of this new compound is under active investigation.

A series of 6-(hydroxylamino)purine and -1-deazapurine nucleosides were synthesized and tested for their antitumor and adenosine deaminase inhibitory activity. All the examined molecules displayed an in vitro activity comparable to that of the reference compounds 6-(hydroxylamino)-9-beta-D-ribofuranosylpurine (HAPR) and ara-A, their ID50 ranging from 0.9 microM to approximately 100 microM. The 6-hydroxylamino derivatives of 1-deazapurine 9, 12, and 17 and also the blocked compound 13 are inhibitors of ADA whereas the purine derivatives 4 and 6 and the nitro compounds 11 and 16 are resistant to the enzyme. 7-(Hydroxylamino)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3H-imi dazo[4,5- b]pyridine, the less cytotoxic but the most active ADA inhibitor in the series (Ki = 2.7 x 10(-7)), greatly potentiates the antitumor activity of ara-A in vitro.

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ABSTRACTulocyte colony-stimulating factor. 17,18 This DLT was expected considering the cell cycle effect of danusertib. Phosphorylation of the histone H3 tail is critical for mitosis to progress and aurora B kinase is a primary mitotic kinase responsible for the phosphorylation on serine 10. 19 Thus, loss of histone H3 phosphorylation can be used as a pharmacodynamic biomarker of aurora kinase inhibition. In a phase 1 trial in solid tumors, diminished phosphorylation of histone H3 was demonstrated in concomitant skin biopsies, confirming the pharmacodynamic effects of danusertib.Based on the in vitro activity of danusertib against ABL kinase, including most TKI-resistant mutants, we conducted a phase 1 study of danusertib in adult patients with advanced CML in accelerated or blastic phase (CML-AP or CML-BP) or Ph + ALL, resistant or intolerant to imatinib and/or second-generation TKI. MethodsThe primary objective was to determine the maximum tolerated dose (MTD), and DLT of danusertib administered as a 3-h intravenous infusion daily for 7 consecutive days (days 1 to 7) of a 14-day cycle (schedule A) or daily for 14 consecutive days of a 21-day cycle (schedule B) in adult patients with advanced CML-AP or CML-BP or Ph + ALL, resistant or intolerant to imatinib and/or second-generation ABL kinase inhibitors. The secondary objectives included an analysis of the safety, pharmacokinetics, pharmacodynamics and clinical activity of danusertib.Initially all patients were to be assigned to schedule A, until the MTD was determined. Thereafter patients were to be allotted to schedule B to define the MTD with this schedule. Subjects provided informed consent and were enrolled in the institutionally approved protocol. Dose escalation and modificationsDose escalation was based on a standard "3+3" design. A modified Fibonacci design was followed for the dose escalation scheme. Intra-patient dose escalation was allowed after at least two cycles at the initially assigned dose. Dose modifications for hematologic and non-hematologic toxicities are summarized in the Online Supplementary Data (dose modifications). Toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0. All patients treated were evaluable for toxicity. Dose-limiting toxicity definitionsDLT were defined as events occurring in cycle 1, attributable to the test drug, and included prolonged myelosuppression (cellularity <10%) in the absence of marrow blasts, grade ≥3 non-hematologic toxicity except for nausea/vomiting/diarrhea controlled with supportive care, a significant decrease of left ventricular ejection fraction, and uncontrolled hypertension. Other hematologic toxicities were not included in the definition of DLT. EligibilityAdults (≥ 18 years) with CML-AP, CML-BP, 20 or Ph + ALL, resistant or intolerant to imatinib and one second-generation Abl-kinase inhibitor were eligible. In France, patients had to be resistant/intolerant to both nilotinib and dasatinib in addition to imatinib. Additi...

Summary We evaluated the myelotoxicity and the anti-tumor potential of tallimustine, three of its analogues and carzelesin, with melphalan as reference substance. Tallimustine was tested by clonogenic assays on both human bone marrow (BM) and cord blood (hCB) cells, the other compounds on hCB only. The degree of inhibition of the haemopoietic progenitors GM-CFC, CFC-E and BFU-E was evaluated after exposure to different concentrations. The same schedules were tested on five tumour cell lines. We found that the dose-response curves for tallimustine on BM and hCB cells were similar. Carzelesin was shown to be the most potent of the substances tested and to be the one with the best in vitro therapeutic index; of the distamycin analogues, the one bearing an alpha-bromoacrylic group (FCE 25450) had the best index. For melphalan, tallimustine and carzelesin, the concentration inhibiting the growth of 70% of progenitor cells in vitro (ID70) was similar to the concentrations found in the serum of patients treated at the maximum tolerated dose (MTD). We conclude that hCB cells may be used instead of BM cells for in vitro myelotoxicity tests. Therapeutic indexes can be extrapolated from this model and could help in selecting the most promising analogue for further clinical development. The in vitro-active concentrations are similar to myelotoxic concentrations in patients, suggesting a predictive value for the assay.