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Mechanisms of collateral sensitivity to ftuorouracil of a cis- diamminedichloroplatinumUI)-resistant human non-small lung cancer cell line Sugimoto Y, Ohe Y, Nishio K, Ohmori T, Morikage T, Fujiwara Y et al. Pharmacology Division, Nat. Cancer Ctr. Research Institute, National Cancer Center Hospital, 5-l-l Tsukiji. Chuo-ku, Tokyo 104. Br J Cancer 1992;65: 857-64.

A cisplatin (CDDP)-resistant suhline of a human lung cancer cell line, PC-‘IICDDP, was 4.7-fold more resistant to CDDP than the parent line in a colony-forming assay. The sensitivity of this cell line to anthracyclines, vinca-alkaloid, etoposide, mitomycin C, and bleomycin was similar to that of the parental line, PC-7. However, PC-7ICDDP exhibited 4-fold higher sensitivity to fluorouracil (FUra). Possible mechanisms associated with the collateral sensitivity to FUra were studied in PC-7/CDDP cells. The sensitivity of both cell lines to FUra did not correlate with the effect of FUra on RNA. On the other hand, FUra induced a greater reduction in dTTP pools and more single strand breaks in PC-7ICDDP than in PC-7 cells. These results suggest that the pathway for de nova deoxyribonucleotide synthesis may be a target for FUrainPC-7/CDDPcells. However, inhibitionofthymidylatesynthase after FUra treatment did not correlatewith the DNA-directed activity of FUra. Based on fhe above findings, the decreased salvage synthesis of dl’TP was considered a possible mechanism of the greater reduction of dTTP pools in PC-‘IICDDP cells. However, the activity of dThd kinase was the same‘in both cell lines. In the presence of physiological concentrations of exogenous dThd in the serum, uptake of dThd was less in PC-‘IICDDP cells than that in PC-7 cells. Our data suggest that FUra- induced cytotoxicity inPC-7/CDDPcellsisassociated withtheinhibition of dTTP synthesis and that the decreased uptake of dThd is a possible mechanism of the collateral sensitivity to FUra in PCJICDDP cells.

PhaseIl study ofhigh-dose aclarubicin in previously treated patients with small-cell lung cancer Jensen PB, Larsen SK, Stilbo 1. Department of Oncology 5074, University Hospital Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen. Cancer Chemother Pharmacol 1992;30:219-20.

Aclaruhicin is one of the antitumor anthracyclines (aclacinomycin A) isolated from Streptomyces galilaeus by Oki et al. in 1975. Preclinical evaluation of aclarubicin has revealed several important differences in the drug’s properties relative to the classic anthracyclines doxorubicin and daunorubicin. Cellular uptake of aclarubicin occurs more rapidly, and in contrast to the classic anthracyclines, aclaruhicin does not stimulate topoisomerase H-mediated DNA breaks. Furthermore, only limited, if any cross-resistance with aclarubicin has been demonstrated in the two well-defined doxorobicin-resistant phenotypes. P-gp MDR (P-glycoprotein multidrug-resistant) and at-MDR (altered topoisomerase MDR) cells. Aclarubicingivenona single-b&s schedulebasnot shown clinically relevant activity against solid tumors. In contrast, the drug has demonstrated activity against leukemia. However, these trials have involved the administration of aclalubicin on prolonged schedules over 3-5 consecutive days and at higher cumulative doses. The present report describes a phase II trial of high-dose aclarubicin given on a 3-day treatment schedule to previously treated patients with small-cell lung cancer.

Mitomycin C plus vindesineorcisplatin plus epirubicin in previously treated patients with symptomatic advanced non-small-cell lung cancer Gridelli C. Airoma G, Incoronato P, Pepe R, Palauolo G, Rossi A. Cattedra di Oncologia Medica, II Fat di Medicina, Uniwrsita ’ di Napoli, Via S. PansiniS, I-80131 Napoli. Cancer Chemotha Pharmacol 1992;30:212-4.

A total of 40 previously treated patients with symptomatic advanced non-small-cell lung cancer (NSCLC) were subjected to second-line

chemotherapy with mitomycin C plus vindesine (MV) or cisplatin plus epiruhicin (PE). The 12 patients treated with the MV regimen showed no objective response (OR) or symptom palliation. In the 28 patients who received the PE regimen, we obtained a 25 46 partial response rate, with amelioration of tumor-related symptoms occurring in 35.7% of cases and improvement in the performance staNs beiig noted in 25 96 of subjects. Both regimens were well tolerated. These data show that the administration of cisplatin-based second-line chemotherapy to patients with symptomatic advanced NSCLC may be useful.

Natural interferon alfa BS maintenance therapy for small lung cancer Mattson K, Niiraaen A, Pyrhonen S, Holsti LR, Holsti P, Kumpulainen E et al. Department of Pulmonary Medicine, Helsinki University Central Hospital, Haartmaninkatu 4,00290 Helsinki. Eur J Cancer Part A Gen Top 1992;28:138791.

We performed a 3-armed phase III study between 1982 and 1990 to evaluate low dose naNral interferon alfa (nIFN-6) as a maintenance therapy in small cell lung cancer (SCLC) following induction chemotherapy (CT) and consolidation radiotherapy (RT). All patients received four cycles of CT (cyclophosphamide, vincristine, etoposide), followed by split-course RT (55 Gy in 20 fractions over 7 weeks). 410 patients entered the sNdy. 237 patients who completed induction CT + RT and were classified as responders (complete response + partial response) were randomly assigned to arm I: low dose nIFN-6 (91 patients); arm2: maintenancea’, six cycles ofCAP(cyclophosphamide, doxorubicin, cisplatin) (59 patients); or arm 3: control arm (no maintenance treatment) (87 patients). Halfway through the study the CAP arm was discontinued. There was no difference in median survival between the groups (IFN: 11 months, CAP: 11 months, control: 10 months), but a clear difference in long-term survival and in survival in the limited disease group, favouring nIFN-6 maintenance therapy. Proportional hazards regression analysis also showed a significant effect of IFN treatment on survival. Our results suggest a role for nIFN-6 in maintaining aclinicallydisease-freestahlsachievedwithother treatment modalities.

Radiotherapy

Endohronchial interstitial Au-198 implantation in the treatment of recurrent bronchogenic carcinoma Tomberlin JK, Halperin EC, Kusin P, Leopold K, Bentel G, George S et al. Division ofRadiation Oncology. Duke Universiry Medical Center, P.O. Box 3082, Durham, NC 27710. J Surg Oncol 1992;49:213-9.

Nineteen patients with non-small-cell bronchogenic carcinoma, recurrent following initial conventional external beam radiotherapy, weretreatedwithendobronchialimplantationofAu-198seeds. Seventeen patients were symptomatic with primary symptoms of persistent hemoptysis (9), bronchial obstruction (2). or worsening dyspnea (6). Two patients were asymptomatic and implanted for bronchoscopic evidence of tumor recurrence. The dose delivered was described by three dosimetric parameters: I) the total activity implanted (m Ci); 2) the midbronchial dose point; and 3) the volume of tissue that received > 20 Gy. Response was determined based on a system reflecting the primary indication for the implant. Seven of nine (78 W) presenting with bemoptysis, four of six (67 %) with increasing dyspnea, and one of two with bronchial obstruction responded. The overall median survival was 5.25 months (2.5-10 months 95% confidence interval). There was no clear correlation between any of the dosimetric parameters evaluated and a clinical response to therapy. Technical complications related to the inability to penetrate the scirrhous tumor surface adequately often led to less thanoptimal dosedistribution. Endobronchial Au-198 implantation is associated with a poor calculated dose distribution but is, nonetheless,