Phase I Clinical Trial of a Day-1, -3, -5 Every 3 WeeksPhase I Clinical Trial of Day-1, -3, -5 Every 3 Weeks Schedule with Titanocene Dichloride (MKT 5) in Patients with Advanced Cancer. (Phase I Study Group of the AIO of the German Cancer Society)

Abstract

Background: Titanocene dichloride (TD) is an organometallic compound with antiproliferative properties in vitro and promising antitumor activity in preclinical in vivo models. The drug interferes with DNA, blocks the S/G₂ phase of the cell cycle and shows antiangiogenic properties. The purpose of this study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of a ‘split’ dose administration schedule (days 1, 3, 5 q 3 weeks). Patients and Method: Patients with progressive advanced cancer and a creatinine clearance > 60 ml/min qualified for a treatment with TD after standard therapies (radio-, chemo-, hormone therapy) failed. A total of 10 patients (4 females, 6 males) with a median age of 58 (range 49–68) years were treated with 80 mg/m² TD at days 1, 3 and 5 (repeated at day 22). The drug was administered as light-protected infusion within 1 h. Results: Significant side effects were as follows: nausea/vomiting, appetite loss, renal toxicity (elevation of serum creatinine and proteinuria) and liver toxicity (bilirubin and alkaline phosphatase elevation), but no myelosuppression. At the starting dose (3 x 80 = 240 mg/m² TD), renal (3 patients) or liver toxicity (1 patient) of grade 3 was judged as DLT. No further dose escalation was possible. No objective tumor remission was observed. Conclusion: The tolerability of TD cannot be improved by splitting the total dose in to three treatments every other day. Compared to previous phase I data using a 3-weekly and a 1-weekly schedule, the ‘split’ dose administration allowed no further increase of the total drug dose per treatment cycle. Thus, dose intensification by alterations of the application mode does not seem to be possible.

Synthesis, characterization and structure of the Bis(methyl-cyclopentadienyl)vanadium(IV) carboxylates

“…The titanocene-and vanadocene dichlorides, (C 5 H 5 ) 2 MCl 2 (M = Ti, V), exhibit antitumor activity for a wide variety of human tumors with reduced toxicity [1][2][3][4]. The biological experiments showed that both the water solubility and the stability of bent [(C 5 H 5 ) 2 …”

Inclusion compounds of cystostatic active (C5H5)2VCl2 and (CH3C5H4)2VCl2 with α-, β- and γ-cyclodextrines: Synthesis, EPR study and microbiological behavior toward Escherichia coli

“…All studied complexes are effective in the cell division and embodies a strong inhibition of bacterial growth. From the obtained data, it can be estimated that complexes 1 and 2 are more effective than the antitumor agent TDC [22], which has undergone clinical testing before [4,23]. The true inclusion compounds 4, 5, 7 and 8 show similar biological activity as free vanadocene complexes 1 and 2.…”

Inhibition of cancer cell growth by ruthenium(II) cyclopentadienyl derivative complexes with heteroaromatic ligands

“…The driving force for the studies on organometallics as reagents to fight cancer has certainly been the promising results already obtained for several organotransition-metal compounds which have been evaluated for their therapeutic properties. Dichloride metallocenes (Cp 2 MCl 2 , M = Ti, V, Nb, Mo, Cp = g 5 -cyclopentadienyl) have shown to exhibit antitumor activity against numerous experimental tumors, e.g., Ehrlich ascites tumor, B 16 melanoma, colon 38 carcinoma and Lewis lung carcinoma, as well as against several human tumors heterotransplanted to athymic mice [2]; titanocene dichloride was already in Phase II clinical trials [3], however it was recently abandoned due to problems of formulation [4,5]. Ferrocene derivatives also showed activity against Rauscher leukemia virus and EAT in CF1 mice [6,7] and in P388 leukemia cells [8] reinoculated tumors [9].…”