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Biochemical Pharmacology Feb 1997Telomeres, or chromosome ends, are essential in maintaining chromosomal integrity. Telomeres consist of a short hexameric sequence, 3'-TTAGGG-5', repeated in tandem...
Telomeres, or chromosome ends, are essential in maintaining chromosomal integrity. Telomeres consist of a short hexameric sequence, 3'-TTAGGG-5', repeated in tandem arrays added to chromosomes by the ribonucleoprotein enzyme telomerase. In this study, we assessed whether penclomedine, a novel synthetic pyridine compound presently being evaluated in clinical trials for its anticancer activity, influences telomere fusions (chromosome end-to-end associations) and telomerase activity in cells in culture. We found that penclomedine reduced the mitotic index, induced chromosome end associations in all phases of the cell cycle, and rapidly induced chromatin blebbing in a concentration-dependent manner in both cervical carcinoma (HeLa) cells and in normal human fibroblasts (AG1522). However, the effectiveness of the drug was much more pronounced in HeLa cells. In addition, there was a drug-mediated, concentration-dependent decline in telomerase activity noted in the HeLa cells that correlated with a decrease in mitotic index and an increase in telomere fusions. Interestingly, when the mitotic index, chromatin blebbing, and telomere fusions were compared between the telomerase positive (HeLa) and negative (AG1522) cell types, penclomedine affected chromatin stability to a greater extent in those cells with detectable telomerase activity. In addition, telomerase positive colorectal carcinoma cells with abrogated p53 (RC-10.3 cells) were more sensitive to penclomedine than were telomerase positive cells with wild-type p53 (RKO cells). These studies suggest that penclomedine may have a therapeutic advantage in killing tumor cells that are positive for telomerase activity and defective in p53 function.
Topics: Antineoplastic Agents; Cell Survival; Chromatin; Genes, p53; HeLa Cells; Humans; Mitotic Index; Picolines; Telomerase; Telomere
PubMed: 9065745
DOI: 10.1016/s0006-2952(96)00766-6 -
British Journal of Cancer Mar 19983,5-Dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine (penclomedine, NSC 338720, CRC 88-04) is an alpha-picoline derivative with anti-tumour activity in preclinical... (Clinical Trial)
Clinical Trial
3,5-Dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine (penclomedine, NSC 338720, CRC 88-04) is an alpha-picoline derivative with anti-tumour activity in preclinical models. Penclomedine administration by 1-h intravenous infusion on 5 consecutive days was repeated 3 weekly in the absence of dose-limiting toxicity (DLT) or disease progression. Five dose levels were investigated (22.5-340 mg m(-2) day[-1]). Eight men and eight women were entered, median age 59 years (range 39-73 years), with good performance status (ECOG 0/1) in 11 patients. A total of 13 out of 16 patients had received previous chemotherapy. Common toxicity criteria grade (CTCg) II vomiting was recorded at all dose levels. Neurotoxicity (cerebellar ataxia and dizziness) was the DLT, CTCg III toxicity occurring in three out of three patients treated at 340 mg m(-2) day(-1). CTCg III dizziness was noted in one out of three patients at 250 mg m(-2) day(-1). Neurotoxicity developed during the 1-h infusion and persisted for a variable period (maximum 5 h) after infusion. Prophylactic antiemetic drugs appeared to reduce associated vomiting but did not prevent ataxia. No antiproliferative toxicities were noted and no anti-tumour responses were documented. Penclomedine pharmacokinetic studies confirmed preclinical evidence of extensive apparent distribution (93 l m[-2]) and rapid clearance (41 l h[-1] m[-2]). Purkinje cell loss has been identified in preclinical models after intraperitoneal administration (O'Reilly et al, 1996a) and further clinical development of penclomedine will focus on oral administration.
Topics: Adult; Aged; Antiemetics; Antineoplastic Agents; Cerebellar Ataxia; Dizziness; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Picolines; Treatment Failure; Vomiting
PubMed: 9514062
DOI: 10.1038/bjc.1998.131 -
Cancer Chemotherapy and Pharmacology Sep 2009The purpose of this investigation was to synthesize a series of carbonate and carbamate derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma non-toxic...
PURPOSE
The purpose of this investigation was to synthesize a series of carbonate and carbamate derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma non-toxic metabolite of penclomedine (PEN) seen in patients. DM-PEN has been observed to be an active antitumor agent in mouse human xenograft tumor models and non-neurotoxic in a rat model, however, activity in intracranially implanted human glioma xenograft models have not been reported. The major goal was to identify derivatives that are active in brain tumors.
METHODS
Derivatives were prepared from DM-PEN and evaluated in vivo against human U251 glioblastoma, D54 glioblastoma and MX-1 breast tumor xenografts and mammary tumor 16/C that were implanted in the mammary fat pad or intracranially (IC).
RESULTS
Carbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts.
CONCLUSION
The activity of the carbonates and carbamates against human tumor xenografts in vivo suggests consideration of these two series of derivatives of DM-PEN for clinical development.
Topics: Animals; Antineoplastic Agents; Carbamates; Carbonates; Chromatography, Thin Layer; Humans; Magnetic Resonance Spectroscopy; Mice; Picolines; Rats; Spectrometry, Mass, Fast Atom Bombardment; Spectrophotometry, Ultraviolet; Transplantation, Heterologous
PubMed: 19255760
DOI: 10.1007/s00280-009-0933-9