New cytostatics—more activity and less toxicity

Berger, Martin R.; Richter, Heike; Seelig, Matthias H.; Eibl, Hansjörg; Schmähl, D.

doi:10.1016/0305-7372(90)90039-i

Cited by 16 publications

(10 citation statements)

References 12 publications

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“…There were also no direct effects on ribonucleotide phosphate pools or DNA, RNA, or lipid synthesis. Since dinaline and CI-994 have equivalent antitumor activity [1, 4, 46], these results suggest that CI-994 does not act as an antimetabolite, nor does it directly effect macromolecular synthesis. However, inhibition of CI-994 and dinaline on DNA synthesis measured by [ 3 H]thymidine incorporation has been observed in rat peripheral blood lymphocytes and human colon carcinoma SW707 cells [11, 52].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Induction of Apoptosis in Rat Peripheral Blood Lymphocytes by the Anticancer Drug CI‐994 (Acetyldinaline)

Graziano

Spoon

Cockrell

et al. 2001

BioMed Research International

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CI-994 (acetyldinaline) is an investigational anticancer drug currently in clinical trials. In preclinical safety studies in rats and dogs, CI-994 resulted in significant toxicity to bone marrow and lymphoid tissue. To determine if apoptosis was involved in CI-994 toxicity, peripheral blood lymphocytes were isolated from untreated male Wistar rats and exposed to CI-994 (1, 3, 10, or 30 μM) in vitro for up to 24 hours. Morphological and biochemical features of apoptosis were evaluated using several techniques, and lactate dehydrogenase (LDH) release was measured as an indicator of cell necrosis. No evidence of apoptosis or necrosis was detected in lymphocytes exposed to CI-994 for 4 hours. After 24 hours, concentration-dependent increases in apoptosis characterized by DNA condensation, DNA fragmentation, and/or externalization of phosphatidyl serine were seen at CI-994 concentrations as low as 1 μM and were statistically significant beginning at 10 μM. Ultrastructural analysis confirmed the presence of DNA condensation, DNA fragmentation, cell shrinkage, and membrane blebbing in cells exposed to 30 μM CI-994. After 24 hours, the percent of maximum LDH release from lymphocytes treated with 10 and 30 μM CI-994 was 7% and 15%, respectively, compared with 0% in the controls. In comparison, morphological changes of apoptosis detected by fluorescent microscopy were observed in 79% of the lymphocytes at these two concentrations. Additionally, apoptosis was seen in more than 24% of lymphocytes exposed to 1 and 3 μM CI-994, whereas maximum LDH release was less than or equal to 1% at these concentrations. These results show that apoptosis is the primary mode of cell death in rat lymphocytes exposed to CI-994 in vitro.

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Section: Discussionmentioning

confidence: 99%

“…CI-994 (acetyldinaline; Figure 1) is an investigational anticancer drug with activity in a broad spectrum of mouse, rat, and human tumor models [1, 2, 3, 4, 5]. CI-994 can also potentiate the activity of other standard chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Induction of Apoptosis in Rat Peripheral Blood Lymphocytes by the Anticancer Drug CI‐994 (Acetyldinaline)

Graziano

Spoon

Cockrell

et al. 2001

BioMed Research International

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“…Because chemotherapy is not a cure for the common types of cancer in adults, new chemical entities are urgently needed. A main task of experimental antineoplastic chemotherapy is to identify new active structures and, subsequently, to investigate structure-activity relationships in order to find congeners with an increased therapeutic ratio [5].…”

Section: Introductionmentioning

confidence: 99%

Signal transduction pathways: New targets in oncology

Sweeb

Beijnen

1993

Pharm World Sci

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For many years the main strategies in the development of anticancer drugs were focused on killing tumour cells by means of agents which are blockers of transcription or translocation. However, it is evident that the currently available anticancer drugs, mainly antimetabolites and alkylating agents, cannot cure the most common types of cancer in adults. Therefore, totally new approaches are necessary in cancer chemotherapy research; one of these is disturbing cell signalling pathways involved in growth and malignant transformation. Several studies have concentrated on mechanisms of cell growth and differentiation, control through growth factor receptors and their ligands, oncogenes, proto-oncogenes and other membrane-associated signaling mechanisms. This paper discusses the potential targets in these signaling pathways for novel anticancer drugs.

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“…CI-994 [aka: acetyldinaline; PD 123654; 4-acetylamino-N-(2'aminophenyl)-benzamide] is a novel agent which was tested as one of a series of analogs of the parent compound dinaline [aka: GOE1734; PD104208; 4-amino-N-(2-aminophenyl)benzamide] [1]. Dinaline was originally developed as an anticonvulsant agent [2].…”

Section: Introductionmentioning

confidence: 99%

“…Dinaline was originally developed as an anticonvulsant agent [2]. Its antitumor activity was discovered and reported on in the mid to late 1980s by several investigators [3][4][5][6][7]. It was found to have significant antitumor activity against slowly growing murine solid tumors, human tumor xenografts and was active in the rat Brown Norway Model of Leukemia [8].…”

Section: Introductionmentioning

confidence: 99%

Preclinical antitumor activity of CI-994

et al. 1996

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CI-994 [aka: acetyldinaline; PD 123654; 4-acetylamino-N-(2'aminophenyl)-benzamide] (Figure 1) is a novel antitumor agent with a unique mechanism of action. It is the acetylated metabolite of dinaline, a compound previously identified as having cytotoxic and cytostatic activity against several murine and human xenograft tumor models. CI-994 had activity against 8/8 solid tumors tested (log cell kills at the highest non-toxic dose): pancreatic ductal adenocarcinoma #02 (4.7); pancreatic adenocarcinoma #03 (3.0; 1/6 cures); colon adenocarcinoma #38 (1.6); colon adenocarcinoma #51/A (1.1); mammary adenocarcinoma #25 (1.7); mammary adenocarcinoma #17/ADR (0.5); Dunning osteogenic sarcoma (4.0); and the human prostate carcinoma LNCaP (1.2). CI-994 had the same spectrum of activity in vivo as dinaline. It also behaved similarly in schedule comparison/toxicity trials. Prolonged administration with lower drug doses was more effective than short-term therapy at higher individual doses. If doses were kept between 40 and 60 mg/kg/injection, prolonged administration (> 50 days) was tolerated with no gross toxicity. Doses > or = 90 mg/kg/injection caused lethality after 4-5 days of administration. The maximum tolerated total dose was also increased with smaller individual doses administered for prolonged intervals. Clinical Phase I trials are ongoing with this agent.

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New cytostatics—more activity and less toxicity

Cited by 16 publications

References 12 publications

Induction of Apoptosis in Rat Peripheral Blood Lymphocytes by the Anticancer Drug CI‐994 (Acetyldinaline)

Induction of Apoptosis in Rat Peripheral Blood Lymphocytes by the Anticancer Drug CI‐994 (Acetyldinaline)

Signal transduction pathways: New targets in oncology

Preclinical antitumor activity of CI-994

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