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

Abstract

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...

Lack of nephrotoxicity of oral ammine/amine platinum (IV) dicarboxylate complexes in rodents

“…The effects of i.v. cisplatin were similar to those previously described (Harrap et al, 1980;Jodrell et al, 1991;Ward et al, 1976) in that this agent caused proteinuria, glycosuria, reduced GFR and histological kidney damage in the mouse, and elevated plasma creatinine, elevated plasma urea, reduced creatinine clearance, urinary glucose wasting, increased kidney weight and renal histological damage in the rat. By comparison, i.v.…”

“…cisplatin (mice, 7 mg kg-'; rats, 6.5 mg kg-') and i.v. carboplatin (mice, 120 mg kg-'; rats, 60 mg kg-') were as previously described (Siddik et al, 1986 (Goldstein et al, 1981;Ward et al, 1976) and when cisplatin-induced disturbances in renal function are apparent in the mouse (Jodrell et al, 1991 (Jodrell et al, 1991). In a time-course study, mice were sacrificed at time-points ranging from 2 h to 10 days following treatment and the kidneys were removed and examined histologically.…”

“…In vivo models were used because of the potential for metabolism of ammine/amine Pt(IV) dicarboxylates and difficulties simulating this in vitro. '4C-inulin clearance, histology and renal tubular function were measured as these have been reported as sensitive tests for cytotoxic druginduced kidney damage in rodents (Goldstein et al, 1986;Jodrell et al, 1991). Six p.o.…”

Probing the Folate-binding Site of Human Thymidylate Synthase by Site-directed Mutagenesis

“…In recent years folate analogues have been designed as highly specific and stable TS inhibitors (6). The inhibitor CB3717 was the first folate analogue inhibitor of TS tested in the clinic and although anti-tumor activity was demonstrated, its further development was abandoned due to renal and hepatic toxicity (7,8). The information provided by the crystal structures of TS from bacterial and mammalian sources (9 -18) has led to the design and synthesis of novel analogues of CH 2 H 4 folate, e.g.…”

A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq™ (nolatrexed dihydrochloride) given by 10-day oral administration

“…The first of these, CB 3717, displayed promising clinical activity (Calvert et al, 1986(Calvert et al, , 1987Bassendine et al, 1987;Cantwell et al, 1988), but its development was abandoned because of sporadic and unpredictable nephrotoxicity and myelotoxicity. A successor to CB 3717, raltitrexed (Tomudex™) (Jackman et al, 1991), has been shown to be non-nephrotoxic (Jodrell et al, 1991) and is currently in use clinically in the treatment of patients with metastatic colorectal cancer.…”