Phase I study of the antifolate N10-propargyl-5,8-dideazafolic acid, CB 3717

Sessa, Cristiana; Zucchetti, Massimo; Ginier, M.; Willems, Yvonne; D’Incalci, Maurizio; Cavalli, Franco

doi:10.1016/0277-5379(88)90313-6

Cited by 20 publications

(8 citation statements)

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“…) is a folate based inhibitor of the enzyme thymidylate synthase (TS), which was found to be an active antitumour agent in early clinical trials in patients with breast, ovarian and hepatocellular carcinoma (Calvert et al, 1986;Cantwell et al, 1988;Bassendine et al, 1987). However, the clinical use of CB3717 was limited by its nephrotoxicity, which was observed in Phase I studies of both weekly (Vest et al, 1988) and 3-weekly administration schedules (Calvert et al, 1986;Sessa et al, 1988). Renal toxicity manifested primarily as a reduction in glomerular filtration rate (GFR).…”

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confidence: 99%

“…CB3717-induced nephrotoxicity was thought to be due to the compound's relative insolubility at acid pH. However, despite adequate alkalinisation (pH ,8) of the urine, reductions in GFR (measured using creatinine clearance) of >20%, were still seen in 6/17 (35%) courses in patients treated at 400 mg m2 (Sessa et al, 1988). To circumvent toxicity related to drug precipitation in the kidney, a series of more soluble analogues of CB3717 have been synthesised.…”

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The renal effects of N10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694, in mice

Jodrell

Newell²,

Morgan³

et al. 1991

Br J Cancer

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Summary N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid (ICI D1694) is an analogue of the thymidylate synthase inhibitor, N'°-propargyl-5,8-dideazafolic acid (CB3717). CB3717 was found to be active in early clinical studies, but its use was limited by nephrotoxicity. ICI D1694 is a more potent antitumour agent than CB3717 and is also more water soluble. Previous studies have shown ICI D1694 to be non-toxic to the kidney following a single administration but its renal effects after chronic administration are unknown. To assess these effects, and further define the time course and dose relationship of CB3717-induced renal damage, an assay of glomerular filtration rate (GFR) has been developed which can be used in mice and hence in the screening of novel compounds. The '4C-inulin clearance assay developed was used to show a linear relationship between CB3717 dosage and renal damage (r=-0.989) following a single bolus dose (50-200mgkg-'), in mice. CB3717-induced renal damage is persistent (>6 weeks) and renal scarring was noted. ICI D1694 has been shown to be non-nephrotoxic following weekly administration of 250 mg kg-' for 6 weeks. Measurement of GFR has been shown to be a more sensitive indicator of impaired renal function than plasma urea and creatinine concentration, and the measurement of plasma creatinine concentration in particular, appears to be without value in the screening of potential nephrotoxins in certain mouse strains.Nl'-propargyl-5,8-dideazafolic acid (CB3717, Figure l.i.) is a folate based inhibitor of the enzyme thymidylate synthase (TS), which was found to be an active antitumour agent in early clinical trials in patients with breast, ovarian and hepatocellular carcinoma (Calvert et al., 1986;Cantwell et al., 1988; Bassendine et al., 1987). However, the clinical use of CB3717 was limited by its nephrotoxicity, which was observed in Phase I studies of both weekly (Vest et al., 1988) and 3-weekly administration schedules (Calvert et al., 1986;Sessa et al., 1988). Renal toxicity manifested primarily as a reduction in glomerular filtration rate (GFR). However, tubular damage was also identified by the measurement of the urinary enzymes, N-acetyl glucosaminidase (NAG) and leucine aminopeptidase (LAP). A >20% reduction in GFR was observed in seven of 12 (58%) patients receiving more than 400 mg m2 CB3717. In addition, urinary NAG and LAP levels were elevated in 50% of patients studied, although this elevation was not dose related (Calvert et al., 1986). CB3717-induced nephrotoxicity was thought to be due to the compound's relative insolubility at acid pH. However, despite adequate alkalinisation (pH ,8) of the urine, reductions in GFR (measured using creatinine clearance) of >20%, were still seen in 6/17 (35%) courses in patients treated at 400 mg m2 (Sessa et al., 1988). To circumvent toxicity related to drug precipitation in the kidney, a series of more soluble analogues of CB3717 have been synthesised. In addition to being devoid of renal toxic...

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confidence: 99%

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confidence: 99%

The renal effects of N10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694, in mice

Jodrell

Newell²,

Morgan³

et al. 1991

Br J Cancer

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“…The antifolates, like natural folates, are eliminated via the kidney (Azarnoff et al, 1974;Sessa et al, 1988;Beale et al, 1998;Rinaldi et al, 1999). Despite the dominant role of FRs in renal elimination of natural folates, their involvement in the renal elimination of antifolates has not been studied.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Binding of Folates and Antifolates to Brush-Border Membrane Vesicles Isolated from Human Kidney

Damaraju

Hamilton²,

Seth-Smith³

et al. 2004

Mol Pharmacol

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Antifolates such as methotrexate, raltitrexed, and pemetrexed are among the most effective and widely used anticancer drugs. The antifolates are also among the most unpredictable of anticancer drugs with respect to pharmacokinetics and toxicity. In this study, we assessed the binding of folates and antifolates to the folate receptors (FRs) of human proximal tubules and the effects of pH on binding.

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“…It enters the cell by means of the reduced folate carrier and requires polyglutamation for its activity. In phase I studies, responses were noted in lung and breast cancers, although renal toxicity was seen to be unpredictable and severe (Sessa et al, 1988). Subsequent phase II trials confirmed this and the development of the drug was discontinued (Cantwell et al, 1988).…”

Section: Nucleoside Analoguesmentioning

confidence: 99%

New antimetabolites in cancer chemotherapy and their clinical impact

1998

Br J Cancer

126

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Summary It is almost 50 years since antimetabolites were first found to have clinical antitumour activity, with Farber's discovery that aminopterin could cause remission in acute leukaemia. In the following 10 years, methotrexate, 6-mercaptopurine and 5-fluorouracil (5-FU) found their way into clinical practice. Subsequently, cytosine arabinoside was found to have activity in acute leukaemia, but, until recently, other significant developments have involved optimizing the efficacy of existing antimetabolites, including the use of leucovorin with methotrexate or 5-FU. Recently, new antimetabolites have become a fertile area for anti-cancer drug research. Gemcitabine (GEMZAR®) has emerged as an important new agent in several tumour types, including pancreatic, non-small-cell lung, bladder, breast and ovarian cancers. Capecitabine is an intriguing new prodrug, offering tumour selectivity and prolonged tumour exposure to 5-FU. More potent thymidylate synthase inhibitors have also emerged; raltitrexed is now commercially available for the treatment of colorectal cancer. Others under development include LY231514, which has other sites of action, hence the acronym MTA (multi-targeted antifolate). A novel target is glycinamide ribonucleotide formyltransferase (GARFT) and LY309887 and AG2034 are undergoing clinical investigation as GARFT inhibitors. A critical element with LY309887 appears to be co-administration of folate. It seems entirely possible that several novel antimetabolites will establish themselves in clinical practice in future for the treatment of solid tumours.

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Phase I study of the antifolate N10-propargyl-5,8-dideazafolic acid, CB 3717

Cited by 20 publications

References 4 publications

The renal effects of N10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694, in mice

The renal effects of N10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694, in mice

Characterization of Binding of Folates and Antifolates to Brush-Border Membrane Vesicles Isolated from Human Kidney

New antimetabolites in cancer chemotherapy and their clinical impact

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