³¹P NMR study of cisplatin‐ and doxorubicininduced changes in tumour metabolism in rats with a cisplatin‐sensitive or ‐resistant immunocytoma

Abstract

The response of tumours to treatment with the cytostatic drugs cisplatin (CDDP) or doxorubicin (DXR) was followed in vivo by 31P NMR spectroscopy. A CDDP-sensitive parent line (IgM-I) and a CDDP-resistant subline (IgM/CDDP) of the IgM-immunocytoma grown s.c. on LOU/M WsL rats were used. Animals from both tumour groups (n = 33) were divided into 3 subgroups: CDDP-treated (1 mg/kg), DXR-treated (10 mg/kg) and control. In 3 out of the 4 treated subgroups where the tumours regressed to less than one half of the initial size, 31P NMR spectroscopy revealed alkaline shifts of 0.31-0.41 pH units at day 4, while the ratio of nucleoside triphosphate to Pi in the tumours, increased continuously to 250-435%. Following CDDP treatment, the 31P NMR spectra of the non-responding IgM/CDDP tumours showed a similar pH increase (0.37 units). The ratio of NTP/Pi showed a temporary decrease to 63 +/- 14% SEM at day 1, which was followed by a recovery to 130 +/- 12% at day 2 and 119 +/- 15% at day 4. The control tumours showed no change in pH and a gradual decrease in the ratio of NTP/Pi. In DXR-treated rats the concentrations of DXR in the immunocytoma tumour and its subline were similar, but in the CDDP-treated rats the IgM-I tumours contained significantly higher levels of platinum than the IgM/CDDP tumours, both measured at 3 and 4 days after administration. The continuous increase in NTP/Pi ratio observed in the responding tumours, is a phenomenon characteristic of tumour regression, while the early temporary decrease in tumour NTP/Pi ratio could be associated with resistance to CDDP. Whether the reported response-specific spectral change applies to other tumour types and other treatment regimens remains to be established.

Multinuclear MR investigation of the metabolic response of the murine RIF‐1 tumor to 5‐fluorouracil chemotherapy

“…Significant increases in tumor pH as we observed during the days after treatment with 5FU (see Table 1 ) have been reported for tumors treated with cyclophosphamide (35 ), cisplatinum ( 3 6 ) , doxorubicin (36,37), and methotrexate (38). The decreases in the total level of MR visible phosphate (2) and the increases in tumor pH strongly suggest that 72 h after chemotherapy, the tumors have become more necrotic than before treatment.…”

“…( 3 9 ) and in necrotic human tumors by Oberhaensli et al, (40). The observation that the extent of the pH increase in the tumors did not correlate with tumor response is in line with the similar cisplatin-induced pH increases in cisplatin-sensitive and -resistant IgM immunocytomas (36). Evelhoch et at., however, observed adriamycin induced pH increases which were specific for adriamycin-sensitive munne mammary adenocarcinomas ( 3 7 ) .…”