32

121 122

IS ENlZOCEINi3 HYPERACTIVITY A FAVOURABLB PEOGNOSTIC FACTOR IN TNR -PIG TltEAlMENT OF SINtNCNCGRNIC CARCINGNA? G.Francini, M.Clerici*, R.Petrioli, S.Marsili, A.Aquino Institute of Medical Pathology, Medical Oncology Division, University of Siena, *S.&r10 Borroneo Hospital, Milan, Italy.

It is known that bronchogenic cancer (BC) can secrete several bormonally active substances structurally similar to parathyroid hormone (FTPH) and calcitonin (CT). It is unknown if hormonal secretion may be an independent prognostic factor in bronchogenic carcinoma.

We studied 264 patients with Bc: 184 with extensive disease and 80 with limited disease in order to evaluate the incidence of increased iF’TH or iCT levels. Histological types of SC were: small cell (SC) in 34 patients and non small cell (“SC) in 230. The levels of iFTH were found to be elevated in 60 cases (22.7%). The levels of iCT were found to be elevated in 73 patients (27.6%). Of the 184 patients with extensive disease 116 were suitable for treatment by chemotherapy and/or radiotherapy. The interrelationships between pretreatment clinical and laboratory variables on response and survival were explored bu multiple regression analysis.

The results seem to show a greater partial remission t complete remission in the hormone secreting group than in the group with normal or absent hormonal secretion (“SC 26% vs 16%; SC 78% vs 66%). In multivariate analysis hormonal secretion showed to be an independent prognostic factor for survivsl.

To explain the different response of the two groups to treatment we need to consider that hormone secreting lung cancers seem to be more chemosensitive. Perhaps the neoplastic population has less cellular heterogeneity than tumors with little or no endocrine activity.

123

Resistance Modulation and Its Biochemical Mechanisms in Acquired Cisplatin (CDDP) Resistant Lung Cancer Cell Line by Pentoxifylline (PTX). Lai, S. Al., Jacqueline, W-P2, Perng, R. P.I Chest Department, Veterans General Hospital, Taipei, TaiwanI, Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan2.

We established the acquired CDDP resistant cell line H- 460/CDDPgO from a large cell lung cancer cell line NCI-H460, which presented 20 fold CDDP resistance phenotype. Resistance modulation could be achieved by PTX combine with CDDP treatment. Early entry of G2/M phase of cell cycle were noted when DNA damage was potentiated by PTX (1 mM) administration immediately following equimolar CDDP (20 uM) treatment in the resistant cells. Premature activation of cdc2-associated histone Hl kinase activity achieved the peak level at 8-12 h after PTX exposure following CDDP treatment which is correlated to the alteration of cell cycle distribution. Also the enhanced cytotoxic activity was confirmed by the evidence of oligonucleosomal DNA fragmentation observed within 24 h after CDDP combined with PTX treatment rather than 72 h (CDDP alone). The timing of apoptotic cell death is similar to that of the parental cells treated with the same condition.

Our findings suggest that PTX enhance the CDDP cytotoxicity in acquired CDDP-resistant cells, the resistance modulation is through abrogation of CDDP-induced cell cycle arrest and permiting the resistant cells to transit G2/M phase prematurely. This imply the possible clinical application of PTX as a resistance modulator.

MISCELLANEOUS

124

EXPRESSION OF DT-DIAPHORASE IN LUNG CANCER CELL LINES AND SENSITIVITY TO THE NOVEL BIOREDUCTIVE INDOLOQUINONE E09 UNDER OXIC AND HYPOXIC CONDITIONS. R. Milroy, J. A. Plumbl, S. W. Banham and P. Workmant. Departments of Respiratory Medicine, Stobhill Hospital and 2Royal Infirmary, Glasgow and ‘CRC Department of Medical Oncology, University of Glasgow, Beatson Laboratories, Garscube Estate, Bearsden, Glasgow, U.K.

Bioreductive agents are pro-drugs that require metabolic activation. Generally, this is thought to occur by l-electron reducing enzymes such as cytochrome P450 reductase. This pathway is oxygen sensitive and enhanced toxicity is observed under hypoxic conditions. Indoloquinone EO9 is a novel bioreductive agent which shows structural similarities to mitomycin C but is less myelosuppressive. It is currently undergoing Phase 1 evaluation under the auspices of the EORTC. Eo9 requires metabolic activation and has been shown to be a substrate for the obligate 2-electron reducing enzyme DT-diaphorase (DTD). We have investigated the role of DTD in the cellular toxicity of E09 in a panel of lung cancer cell lines. The cell lines showed a wide range of DTD activities. Levels in the 4 non-small-cell lung cancer cell lines tended to be higher (55-7847 nmole/min/mg) than the 10 small-cell lines (l-S% nmolelminlmg). Enzyme activity did not correlate with the treatment status of the patient from whom the cell line was established. When exposed to EO9 in air, cell lines with high levels of DTD were markedly more sensitve than those with low levels of DTD and a clear correlation between DTD activity and sensitivity to ED9 was observed. However, under hypoxic conditions cell lines with low levels of DTD activity showed a large increase in sensitivity (up to 40 fold) whilst cell lines with high levels of DTD showed little if any increase in sensitivity.

Thus E09 can be metabolised by DTD to a toxic species in air. However, a similar degree of activation is observed under hypoxic conditions in cell lines with low levels of DTD; presumably by l- electron reduction. Hence E09 can target tumours with hypoxic areas and, in addition, tumours with high levels of expression of DTD.

ENHANCED RECRUITMENT OF PYRIMIDINE SALVAGE PATHWAYS IN N-417 SMALL CELL LUNG CANCER CELL EXTRACTS VIA “F NMR AND “P NMR. RH Knop’, NV Pederson”, WM Millei’, JA Zanghi”, T Victoi, A Bergman’, J Guerrieri”. Medical Oncology’, Dept. Chem. Engineering”. Evanston Hospital, Northwestern University, Evanston, IL60201.

3’P NMR extract spectra of N-417 Small Cell Lung Cancer cells cultured with fuorouridine (FUrd) show that peaks are identified as FUTP, FUDP, FUDP-glucose, FUDP-glucuronate, FUDP-GlcNAc, and FUDP-GalNAc (FUDP-HexNAc). Our prior 3’P NMR studies of N-417 cells showed an increased levels of nuclectide sugars by utilization of UTP even when de novo pyrimidine synthesis is decreased (Can Res, 523782, 1992). We now show that FUrd treated N-417 cells generate high levels of FUTP with no increase in FUDP-HexNAc levels. With FUrd/GlcN a 66% increase of FUDP-GlcNAc and FUDP-GalNAc occurs. The ratio of FUDPHexNAc:UDP-HexNAc is 4:i. PALA blocks the GlcN induced synthesis of UDP-HexNAc (UTP depletion) and cells pretreated with PAIA followed by FUrd/GlcN produce an 8:i ratioof FUDP-HexNAc:UDP-HexNAc. The levels of FUDP-HexNAc generated under these conditions are higher than that achieved by the same reaction in any other human tumor cell line. The results of altered FUTPAJTP ratios plus increased levels of FUDP-HexNAc in cells that do not produce FdUMP has not yet been explored. The N-417 SCLC cell line appears to be a good model for this.

Supporfeci by the Jean Ruggles Romaser Research Endowment (R/-K), the A/yce Salerno NMR Lab (AS), and NSF- grant BCS-9058418 (WMM).