Antitumor Effect of DX‐8951, a Novel Camptothecin Analog, on Human Pancreatic Tumor Cells and Their CPT‐11‐resistant Variants Cultured in vitro and Xenografted into Nude Mice

Abstract

DX‐8951 is a novel water‐soluble derivative of camptothecin. We evaluated the effects of DX‐8951 on the growth of several pancreatic tumor cell lines in vitro and in vivo. In vitro cytotoxic activity of DX‐8951 against SUIT‐2 and KP‐1N cells, as indicated by IC50 value, was several times more potent than that of SN‐38, an active metabolite of CPT‐11, and dozens of times more potent than that of SK&F104864 (topotecan). DX‐8951 also showed the greatest cytotoxicity against CPT‐11‐resis‐tant variants, SUIT‐2/CPT‐11 and KP‐1N/CPT‐11 cells, and the cross‐resistance of these cells to DX‐8951 was lower than that to SN‐38 and SK&F104864. Topoisomerase 1 inhibitory activity of DX‐8951 was about three‐fold stronger than that of SN‐38, as measured in crude nuclear extract obtained from SUIT‐2 cells. DX‐8951 induced DNA fragmentation, a specific feature of apoptosis, in SUIT‐2 cells more effectively than SN‐38. DX‐8951 exhibited potent antitumor effects against SUIT‐2 in a solid tumor model and in a liver metastasis model, in which tumor cells were xenografted sub‐cutaneously and intrasplenically, respectively, into nude mice. The in vivo effects were closely similar to or somewhat superior to those of CPT‐11, DX‐8951 also showed significant antitumor effects against SUIT‐2/CPT‐11 solid tumors, against which CPT‐11 had no effect. These results suggest that, on the basis of its strong antitumor activity and effectiveness against CPT‐11‐resistant tumors, DX‐8951 may be a useful therapeutic agent in the treatment of human cancer. The potent cytotoxicity of DX‐8951 may result from strong inhibition of topoisomerase I, which may then trigger apoptotic cell death.

Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity

“…It has been suggested that DX-8951f is less affected by mechanisms of resistance described for other camptothecins. For example, DX-8951f has shown significant antitumour effects against cell lines and xenografts, in which CPT-11 was not effective (Takiguchi et al, 1997;Kumazawa et al, 1998). It may also overcome Pgp-mediated multidrug resistance, as it is highly effective against cell lines overexpressing the P170-glycoprotein transporter both in vitro and in vivo (Mitsui et al, 1995;Kumazawa et al, 1998).…”

A phase II clinical and pharmacokinetic study of intravenous exatecan mesylate (DX-8951f) in patients with untreated metastatic gastric cancer

“…In cell-based cytotoxicity assays, DX-8951f showed impressive antiproliferative activity against a wide range of tumor cell lines including breast, lung, gastric, and colon cancers [8,9,[23][24][25], and was quite effective in inhibiting the growth of clonogenic cells from various human tumors [26]. In vivo, DX-8951f was shown to have broad antitumor activity against a large panel of human tumor xenografts in nude mice, including SN-38-and vincristine-resistant tumors [8][9][10]. An integrated clinical development plan of DX-8951f led to parallel phase I studies evaluating six dosing schedules and the daily times five every 3 weeks schedule was selected for phase II studies.…”

“…Exatecan mesylate (DX-8951f; Daiichi Pharmaceutical Co., Ltd., Japan) is a synthetic camptothecin analogue (Figure 1) that is a more potent inhibitor of topoisomerase I than camptothecin, topotecan, and the active metabolite of irinotecan, SN-38 [8][9][10]. In preclinical studies, DX8951f demonstrated broad antitumor activity compared with available camptothecin analogues [8][9][10].…”

“…In preclinical studies, DX8951f demonstrated broad antitumor activity compared with available camptothecin analogues [8][9][10]. Cyclical dosing at lower doses demonstrated higher antitumor activity compared to single dose administration [11].…”

Consistent Liver Metastases in a Rat Model by Portal Injection of Microencapsulated Cancer Cells

“…Moreover, many cell lines do not generate consistent liver metastases when administered as single cell suspensions (7)(8)(9). An additional obstacle with this model is that tumor growth occurs in sites other than the liver, such as the injected spleen and/or peritoneum (10). In fact, these undesirable tumor growths make experiments focusing on liver metastases difficult to interpret and largely inhibit the appearance of liver metastases (11,12).…”