Disease relevance of Tallimustine

• The dominant dose-related toxicity of tallimustine was neutropenia, becoming dose limiting at 250 micrograms/m2/day [1].
• Tallimustine, an effective antileukemic agent in a severe combined immunodeficient mouse model of adult myelogenous leukemia, induces remissions in a phase I study [2].
• Future studies may combine tallimustine with other agents known to be active against AML, and investigate its activity in other hematological malignancies [2].
• In SCID mice grafted with a human myelomonocytic leukemia cell line, tallimustine resulted in complete remission of disease in most mice at tolerable dosages ranging from 0.86 to 3.0 mg/kg/day for 3 days and was combined effectively and safely with a 2-day schedule of high-dose ara-C [2].
• Tallimustine in advanced previously untreated colorectal cancer, a phase II study [3].

High impact information on Tallimustine

• Distamycin A and tallimustine inhibit TBP binding and basal in vitro transcription [4].
• The alkylating benzoyl mustard derivative tallimustine (FCE 24517) has powerful anti-tumor activity [4].
• By comparing the methylation interference patterns of different sites, performing electrophoretic mobility shift assays (EMSA) with IC-substituted oligonucleotides and competition experiments with the minor groove binding (MGB) drugs distamicin A, tallimustine and Hoechst 33258 we show that NF-Y makes key minor groove interactions [5].
• These findings suggested a cooperative binding model for tallimustine in which one molecule noncovalently resides in the DNA minor groove and locally perturbs the DNA structure, thereby facilitating alkylation by a second tallimustine of an exposed guanine on another side of the DNA [6].
• Combinatorial identification of a novel consensus sequence for the covalent DNA-binding polyamide tallimustine [6].

Chemical compound and disease context of Tallimustine

• The screening of other distamycin derivatives, which maintain antitumour activity and exhibit much lower toxicity against human bone marrow cells than tallimustine led to the identification of brostallicin (PNU-166196) which is currently under early clinical investigation [7].

Biological context of Tallimustine

• In contrast, the S-phase cells treated with tallimustine were not perturbed during the DNA-synthesis phase progression, and were blocked in G2 only after they had passed through the G1/S transition of a new cell cycle [8].
• In cells which were in G1 or G2/M phases during drug treatment, tallimustine and L-PAM caused similar accumulation in G2 [8].
• Despite the high specificity at the nucleotide level, tallimustine did not differentiate among bulk DNA and three discrete AT-rich regions of genomic DNA examined by quantitative PCR stop assay with lesion frequencies ranging from 0.23 to 0.39 lesions/kbp at 25 microM drug [9].
• However, the 5'-TTTTGPu-3' motifs targeted by tallimustine are relatively infrequent and scattered throughout the genome [9].
• 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) [10].

Anatomical context of Tallimustine

• In general, the hematopoietic system response to tallimustine was dampened, with no overshoots, suggesting either lasting effects or extensive cytotoxicity from the early to late precursors of all lineages [11].
• Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment [12].
• In addition, p53-deficient mouse fibroblasts lacking PMS2 were as sensitive to brostallicin as PMS2-proficient cells, but were 1.6-fold resistant to tallimustine [13].
• Tallimustine was tested by clonogenic assays on both human bone marrow (BM) and cord blood (hCB) cells, the other compounds on hCB only [10].
• We have analysed the effects of tallimustine and distamycin on cell growth and differentiation of K562 cells [14].

Associations of Tallimustine with other chemical compounds

• By coupling bromodeoxyuridine (BUdR) immunoreaction with biparametric flow-cytometric (FCM) analysis, we investigated the cell-cycle phase perturbation induced by tallimustine or L-PAM, considering separately the cells which, during the 1-hr treatment, were in the S phase or in G1-G2/M phases of the cell cycle [8].
• Phase I study of the novel distamycin derivative tallimustine (FCE 24517) [12].
• Decreased tyrosine phosphorylation in tumour cells resistant to FCE 24517 (tallimustine) [15].
• The correlation between cytotoxicity and alkylation pattern suggests that tallimustine exerts its cytotoxicity through DNA sequence-specific alkylation of the adenine located in the sequence 5'-TTTTGA [16].
• The design, synthesis and in vitro activities of a series of cinnamoyl nitrogen mustard pyrazole analogues of tallimustine 8-13, in which the amidino moiety has been replaced by moieties of different physico-chemical features are described, and the structure-activity relationships are discussed [17].

Gene context of Tallimustine

• We report that the sensitivities of MLH1-deficient and -proficient HCT116 human colon carcinoma cells were comparable after treatment with brostallicin, while tallimustine resulted in a three times lower cytotoxicity in MLH1-deficient than in -proficient cells [13].
• MSH2-deficient HEC59 parental endometrial adenocarcinoma cells were as sensitive as the proficient HEC59+ch2 cells after brostallicin treatment, but were 1.8-fold resistant after tallimustine treatment as compared to the MSH2-proficient HEC59+ch2 counterpart [13].
• These data indicate that the effects of Tallimustine on cell cycle progression in yeast are mediated by the RAD9 gene product [18].
• The results obtained showed that PNU 151807 seems to have a mechanism of action completely different from that of its parent compound tallimustine, possibly involving the inhibition of cyclin-dependent kinases activity, and clearly indicate PNU 151807 as a new non-covalent minor groove binder with cytotoxic activity against cancer cells [19].
• Accumulation of gamma-globin mRNA and induction of erythroid differentiation after treatment of human leukaemic K562 cells with tallimustine [14].

Analytical, diagnostic and therapeutic context of Tallimustine

• Tallimustine is inactive in patients with previously treated small cell lung cancer. A phase II trial of the National Cancer Institute of Canada Clinical Trials Group [20].
• A sensitive and reproducible HPLC method for the determination of tallimustine (I) in human plasma has been developed and validated [21].
• Determination of tallimustine in human plasma by high-performance liquid chromatography [21].
• The CC-1065 derivatives, Adozelesin and its prodrug, Carzelesin, and Tallimustine were found to be very effective against several murine tumours and human xenografts, and were shown to be active against experimental tumours that were resistant to other antineoplastic agents, including conventional alkylating agents [22].

References