Antitumor activity and toxicity in animals of N-7[2-(4-nitrophenyidithio) ethyl] mitomycin C (BMY-25067)

Bradner, William T.; Rose, William C.; Schurig, John E.; Florczyk, Alexander P.

doi:10.1007/bf00171978

Cited by 14 publications

(9 citation statements)

References 9 publications

(9 reference statements)

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“…BMS-181174 had slight activity against a subline of L1210 that was partly resistant to MMC, but it was inactive against highly MMC-resistant P388. In these studies at their respective maximum non-lethal doses in mice, BMS-181174 caused less neutropenia than MMC and was also less neutropenic and much less thrombocytopenic in ferrets (Bradner et al, 1990). BMS -181174 R = -NH(CH2)2-SS-_pC6H4N02 Figure 1 Chemical structures of Mitomycin-C and BMS-181174 We have undertaken phase I evaluation of BMS-181174, to assess the maximum-tolerated dose (MTD), toxicity and pharmacokinetic parameters of the drug after intravenous injection every 28 days.…”

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confidence: 87%

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Phase I study of the mitomycin C analogue BMS-181174

Macaulay

O’Byrne²,

Green³

et al. 1998

Br J Cancer

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Summary BMS-1 81174 is an aminodisulphide derivative of Mitomycin C (MMC) with activity against a range of tumour cell lines and xenografts, including MMC-resistant tumours. In a phase I study of 82 patients with confirmed malignancy, we administered BMS-181174 at doses of 0.8-75 mg m-2 by intravenous injection every 28 days. At least three patients were evaluated at each dose level, and 174 courses were administered. The pharmacokinetics were dose linear at BMS-1 81174 doses of 11.5-75 mg m-2 and the drug appeared to undergo wide distribution. The maximum-tolerated dose was 65 mg m-2 in previously treated patients and 75 mg m-2 in chemotherapy-naive cases. The dose-limiting toxicity was myelosuppression, particularly thrombocytopenia, which was prolonged and cumulative. Three patients treated at 65-75 mg m-2 died suddenly with evidence of pneumonia/pneumonitis, thought to be drug-related. Other toxicities included thrombophlebitis, possible cardiotoxicity (asymptomatic, reversible decline in left ventricular function) and renal impairment. The partial response rate was 5% (4 out of 82) overall, and 9% (3 out of 32) in patients treated at 65-75 mg m-2. Responses occurred in treated and previously-untreated patients, including cases of colorectal cancer, non-small-cell lung cancer, ovarian cancer and adenocarcinoma of unknown primary site. BMS-181174 has anti-cancer activity but, because of its toxicity, particularly pneumonitis and thrombophlebitis, no phase 11 studies are planned.

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confidence: 87%

“…The anti-tumour effects of BMS-1 81174 have been evaluated in vivo (Bradner et al, 1990). Compared with MMC, it had superior activity against B 16 melanoma when both drug and tumour were given intraperitoneally, or when given intravenously against subcutaneous tumour.…”

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confidence: 99%

Phase I study of the mitomycin C analogue BMS-181174

Macaulay

O’Byrne²,

Green³

et al. 1998

Br J Cancer

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“…Toxicological studies have revealed that BMS-181174 is relatively less toxic than MMC (Bradner et al, 1990). Preclinical studies, including those from our laboratory, have shown that BMS-181174 is significantly more cytotoxic than MMC in vitro against a variety of tumour cells (Dusre et al, 1990; Xu and Singh, 1992;Xu et al, 1994a;Rockwell et al, 1995).…”

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confidence: 95%

“…This has led to the synthesis of analogues, in an attempt to identify anti-cancer agents with fewer side-effects and/or superior anti-tumour activity than MMC (Doyle and Vyas, 1990). BMS-181174 is one such MMC analogue (see Figure 1 for structures of MMC and BMS-181174) that has shown promise preclinically (Doyle and Vyas, 1990;Bradner et al, 1990; Dusre et al, 1990; Xu and Singh, 1992;Rockwell et al, 1995), and is currently in clinical trials as an anti-cancer agent (Verweij et al, 1993;Talbot et al, 1994).…”

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confidence: 99%

“…Preclinical studies, including those from our laboratory, have shown that BMS-181174 is significantly more cytotoxic than MMC in vitro against a variety of tumour cells (Dusre et al, 1990; Xu and Singh, 1992;Xu et al, 1994a;Rockwell et al, 1995). It is important to point out, however, that BMS-181174 has not always exhibited superior anti-tumour activity in vivo compared with MMC Received 13 November 1996 Revised 10 February 1997 Accepted 11 February 1997 Correspondence to: SV Singh (Bradner et al, 1990;Rockwell and Kelley, 1996). For example, Bradner et al (1990) have documented that, whereas BMS-181174 is relatively superior than MMC against B 16 melanoma, the antitumour activity of this analogue is equivalent to that of the parent drug against P388 and L1210 leukaemia, and M109 lung carcinoma (Bradner et al, 1990).…”

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confidence: 99%

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Characterization of a BMS-181174-resistant human bladder cancer cell line

Xia

Bleicher²,

Hu³

et al. 1997

Br J Cancer

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Summary This study was undertaken to elucidate the mechanism of cellular resistance to BMS-181174, a novel analogue of mitomycin C (MMC), in a human bladder cancer cell line. The BMS-1 81174-resistant variant (J82/BMS) was established by repeated continuous exposures of parental cells (J82) to increasing concentrations of BMS-181174 (9-40 nM) over a period of about 17 months. A 2.6-fold higher concentration of BMS-181174 was required to kill 50% of J82/BMS cell line compared with J82. The J82/BMS cell line exhibited collateral sensitivity to 5-fluorouracil (5-FU), but was significantly more cross-resistant to MMC, melphalan, taxol, doxorubicin and VP-16. NADPH cytochrome P450 reductase and DT-diaphorase activities, which have been implicated in bioreductive activation of MMC, were significantly lower in the J82/BMS cell line than in J82. The cytotoxicity of BMS-181174, however, was not affected in either cell line by pretreatment with dicoumarol, which is an inhibitor of DT-diaphorase activity. These results argue against a role of DT-diaphorase in cellular bioactivation of BMS-181174, a conclusion consistent with that of Rockwell et al (Biochem Pharmacol, 50: 1239-1243. BMS-181174-induced DNA interstrand cross-link (DNA-ISC) frequency was markedly lower in J82/BMS cell line than in J82 at every drug concentration tested. The results of the present study suggest that cellular resistance to BMS-181174 in J82/BMS cell line may be due to reduced DNA-ISC formation. However, the mechanism of relatively lower BMS-181174 induced DNA-ISC formation in J82/BMS cell line than in parental cells remains to be clarified.

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Antitumor activity and toxicity in animals of N-7[2-(4-nitrophenyidithio) ethyl] mitomycin C (BMY-25067)

Cited by 14 publications

References 9 publications

Phase I study of the mitomycin C analogue BMS-181174

Phase I study of the mitomycin C analogue BMS-181174

Characterization of a BMS-181174-resistant human bladder cancer cell line

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