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Clin Trials 198912519-20. Fourteen patients with extenstve-disease non-small-cell lung cancer

(E-NSCLC) were treated with oral 4-demethoxydaunorubicin (idarubi- tin, 4DMDR) at a dosage of 10 mg/m2/d2y x 5 days every 3 weeks. The median cumulative dose was 110 mg/m” (range: 50-1,100). Two pa- tients had stable disease for 12 2nd 56 weeks, respectively, one patient had failed to respond to a doxorubicin hydrochloride (Adriamycin) containing regimen, 2nd one had had no prior therapy. Twelve of the 14 patients had prior radiotherapy, chemotherapy, or both. Median snr- viva1 for this heavily treated group was 16 weeks. Myelosnppression was minimal. Nausea and vomiting occnrrcd in 44% of all courses. No cardiac toxicity 2nd no decrease in cardiac ejection fraction was observed. Weconclude that4DMDR is ineffective in heavily treated E- NSCLC patients. However, the drug’s activity in untreated patients is unknown. Further study of 4DMDR is indicated in patients who have hadnopriorchemotherapyorradiotherapy, withrontineadministration of antiemetic drugs along with pharmacokinetic studies.

S-Fluorouracil infusion and mitomycin combination chemotherapy in the management of patients with advanced non-small-cell lung C2OCel

Weir AB III, Niell HB, Griffin JP. Hemurology-Oncology Section, Veterans Adminisfration Medical Cenrer, Memphis, TN. Am I Clin Gncol, Cancer Clin Trials 1989;12:521-3.

We have carried out a phase II study evaluating the activity of 2 5- flnorouracil drug combination in patients with advanced non-small-cell lung cancer. Patients were given 60 mg/m’of methotrexate i.v. on day 1. On day 2.750 mg/m” of S-flnoronr2cil was administered as a 24-h infusion tily for 3 days. Also on day 3, 10 mg/m’ of mitomycin was given i.v. along with folinic acid. Folinic acid was started on day 3 initially at a dose of 25 mg/m’ intravenously every 6 h for three doses, followedby220-hinfnsionof200mg/m2dailyondays 3 and4. Therapy was repeated every 28 days. Fourteen of 35 patients (40%) experienced 2 partial response to chemotherapy. The median survival of the entire group was 19 weeks. Mncositis was a common side effect but severe leukopenia, anemia, renal insufficiency, 2nd skin ulceration were rare. This study demonstrated that 5-flnorouracil infusion therapy has activ- ity in advanced non-small-cell lung cancer but the responses are not durable. Further studies evaluating differing dose schedules 2nd alter- nate5-flnorouracil infusion-baseddrugcombinations seems warranted.

In vitro evaluation of the potential of aclarubicin in the treatment of small cell carcinoma of the lung (SCCL) Jensen P.B. Vindelov L. Reed H et al. Deportmenr ofOncology, Finsen InsdtutelRigshospitcJer, DK-2100 Copenhagen. Br J Cancer 1989;60:838- 44.

The sensitivity of eight cell lines established from treated and untreated patients with small cell carcinoma of die lung (SCCL) was tested in the clonogenic assay with 1 h 2nd continuous exposure to aclarubicin (ACLA), adriamycin (ADR), dannorubicin (DAU) 2nd mitoxantrone (MIT@. The sensitivity to ADR, DAU and MIT0 covari- ated, 2nd varied with 2 factor of five. The sensitivity to ACLA was independent of the sensitivity to ADR and varied only within a factor of two. Only ACLA showed pronounced increased potency with continn- ons incubation, and ACLA was the most potent drug in the three cell lines least sensitive to ADR. Two resistant cell lines were selected by treating NC&H69 in vitro with DAU. One cell line (9-fold resistant to DAU)expressedlargeamonntsofP-glycoprotein. tbeothercell line(4- fold resistant to DAU) had barely detectable glycoprotein. Both lines acquired resistance to ADR, ACLA and MITO. The cross-resistance to ACLA and MIT0 was only partial and ACLA was still the most potent drug on these lines. The sensitivity to ACLA of the cell lines least sensitive to ADR suggest that ACLA partially circumvents mechanisms of multidrug resistance. Together with the pronounced increase in potency with prolonged exposure these results suggest that ACLA has a mechanism of action different from the ‘classical’ anthracyclines. In this context mitoxantmne is more similar to the classical anthracyclines although its structure is more dissimilar.

The effects of vincristine and doxorubicin on the clonogenic cells of a human lung cancer cell line in methylcelhdose and suspension culture Yamashita Y, Nar2 N, Aoki N. First Deparrmenl oflnrernal Medicine, TokyoMedicalandDen~alUniversity.5-45. Yushimal-chotne,Bunkyo- ku, Tokyo 113. Jpn J Cancer Res (Gann) 1989;80:277-82.

The effects of vincristine (VCR) and doxorubicin (DOX) on the growth of an established line of human lung cancer cells, PC9, were studied in methylcellulose and suspension cultures. The secondary colony formation in metbylcellnlose and recovery ofclonogenic cells in suspension were considered to reflect well the self-renewal of the clonogenic cells. When dose-response curves were obtained for VCR and DGX, the primary clonogenic cells (PEl) were more sensitive than secondary clonogenic cells (PE2) or clonogenic cells in suspension. Repeated exposure to VCR in suspension did not inhibit the exponential growth of the clonogenic cells. These data indicated that both drugs were relatively ineffective in specifically suppressing the self-renewal of the clonogenic cells.

Correlation of in vitro drug-sensitivity testing results with response to chemotherapy and survival in extensive-stage small cell lung cancer: A prospective clinical trial Gazdar AF, Steinberg SM. Russell EK et al. National Cancerlnsdrufe- NavyMedicalOncologyBranch,NovalHospital, Bedesda,MD20814. J Natl Cancer Inst 1990;82:117-24.

We devised a novel clinical protocol for extensive-stage small cell lung cancer (SCLC), selecting chemotherapy whenever possible on the basis of in vitro drug-sensitivity testing (DST) of individual patient’s tumor specimens. Most of the specimens were obtained fmm metastatic sites during routine staging procedures. Increase of tumor cell number by culture in selective media usually was required before DST could be performed. We used the Weisenthal dye exclusion assay to place the seven drugs in rank order and to select the in vitro best regimen (IVBR), a three-drug combination of proved efficacy in SCLC. After initial staging and specimen acquisition, patients received etoposide 2nd cisplatin (primary therapy) and were restaged after 12 weeks. Patient2 with partial or no responses and those relapsing after a complete response to primary therapy were switched to the IVBR if DST data were available. If DSTdata were unavailable, an empiric combination, vincristine-doxorubicin-cyclophosphamide, was administered as sec- ondary therapy. Tumor-containing specimens were collected from 60 to 80 patients (75%). One or more cell lines were established from 28 patients, and DST data were available from 26 patients (33% of total). Several parameters of in vitro drug sensitivity were significantly associated [two-sided P (P,) < ,051 with clinic21 response to primary therapy and also with response to the IVBR and were marginally associated with length of survival (.07 < P,< .08). Sixteen patients (23%) received their IVBR as secondary therapy, and four of these (25%) attained a complete response, compared with three of 43 (7%) who received an empiric regimen (PI = .16). We concluded that (a) selection of individualized chemotherapy is labor intensive but feasible in extensive-stage SCLC; (b) DST data are associated with clinical response to primary therapy and to secondary therapy with an IVBR; and (c) further observations will be required if we are to determine whether there is 2 modest therapeutic benefit to administering the IVBR as 2 second therapy.

The formation and removal of cisplatin (CDDP) induced DNA adducts in a CDDP sensitive and resistant human small cell lung carcinoma (HSCLC) cell line Hospers GAP, De Vries EGE, Mnlder NH. Department of Internal Medicine, University Hospital. Oostersingel59, 9713 EZ Groningen. Br J Cancer 1990;61:79-82.

In DNA digested samples of a CDDP sensitive (GLC,) 2nd an 11 -fold resistant (GLC,-CDDP) hSCLC line, the CDDP induced DNA addncts pt-GG (Pt-(NH,)zd @GpG), Pt-AG (Pt-(NH,),d (pApG)), G-PI-G (Pt-