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Clinical protocols for small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) were devised to prospectively select individualized chemotherapy based on in vitro drug sensitivity testing (DST) of cell lines derived from the patient's SCLC tumor cell lines or the patient's fresh NSCLC tumor. DST data derived from SCLC tumor cell lines were available for 33/115 (29%) patients. The DST-selected chemotherapy regimen was administered to 21 (1 8%) patients, or 64% of patients with DST. In SCLC, the DST-selected chemotherapy was administered either during weeks 13-24 following 12 weeks of etoposide/cisplatin, or at relapse after complete response to etoposide'cisplatin.Several parameters of in vitro drug sensitivity were significantly associated (two-sided P < 0.05) with clinical response to primary therapy and also with response to the DST-selected chemotherapy regimen, but were not associated with survival (P = 0.24). Five patients treated with their DST-selected chemotherapy attained a complete or partial response, compared to 5 of 68 who received an empiric regimen (P = 0.057). A total of 36/165 (22%) NSCLC patients had DST successfully completed. These results directed management for 21 /96 (22%) patients who eventually, received chemotherapy, or 58% of patients with DST. Response to chemotherapy for the patients treated prospectively with their DST-selected chemotherapy regimen 12/27 ; 9%) was not significantly different than the response rate for patients treated empirically with etoposide/cisplatin (10/69; 14%) in the absence of in vitro results to direct chemotherapy (P = 0.73). There was no difference in survival by treatment group for the NSCLC patients. The correlation between in vitro and clinical response was not significant for any individual drug or for all drugs considered together, illustrating the poor predictive value of in vitro testing with currently available chemotherapy in NSCLC.Key words: non-small cell lung cancer, small cell lung cancer, drug resistance, cell survival D 1996 WiIey-Liss, In<.Abbreviations used: ADR, doxorubicin; CCNU, lomustine; CDDP, cisplatin; CR, complete response; CTX, cyclophosphamide; DST, drug sensitivity testing; ECOG, Eastern Cooperative Oncology Group; TVBR, in vitro best regimen; MTX, methotrexate; NM, nitrogen mustard; NSCLC, non-small cell lung cancer; PR, partial response; RPMI, Roswell Park Memorial Institute; VAC, vincristine, doxorubicin, cyclophosphamide; VCR, vincristine; VP-16, etoposide. Received January 16,1996.Address reprint requests to

The extensive metabolizer phenotype of debrisoquine has been associated with increased risk of lung cancer, and it has been proposed that a molecular test for this phenotype is feasible. DNA restriction fragment length polymorphisms of the human debrisoquine 4-hydroxylase gene locus (CYP2D6), and the metabolic phenotype for debrisoquine have been studied in a group of healthy volunteers, a group of lung cancer patients and two control groups (chronic obstructive pulmonary disease patients and patients with cancers at sites other than the lung). Confirmation of four distinct XbaI allelic fragments (44, 29, 16/9 and 11.5 kb), previously identified among caucasians, was obtained. The 29 kb alleles were the most frequently observed in both poor and extensive metabolizers of debrisoquine. Alleles of 44 kb were found with approximately equal frequency among both poor and extensive metabolizers. The data are consistent with the hypothesis that the 11.5 and 44 kb fragments are associated with mutant alleles of the CYP2D6 gene, but the power of phenotype prediction by these alleles was less than that previously reported for a European (Swiss-German) population. Similarly, the data also show that 8% of 29 kb homozygotes are poor metabolizers (indicating that at least 28% of 29 kb fragments are also associated with mutant alleles) and are not therefore informative for predicting the debrisoquine phenotype. The 16/9 allele may represent either wild-type or mutant alleles. Restriction fragments of 44 kb were found more frequently among cancer patients and chronic obstructive pulmonary disease patients (30%) than among the healthy volunteer group (7%). Genotypes observed were not related to lung tumor histology. Furthermore, at least three EcoRI alleles were found to be in linkage disequilibrium with the 'mutant' 44 kb allele. These data suggest that the 44 kb allele can comprise three distinct haplotypes, in contrast to studies of a European population. These studies indicate that no single mutant CYP2D6 allele as determined by EcoRI appears to be associated with lung cancer, despite the findings that these patients are invariably of the extensive metabolizer phenotype.

Promising cancer clinical trials results involving the disruption of early stages of cancer with intervention agents such as tamoxifen or retinoids have led to significant new research interest in developing preventative strategy for the control of epithelial cancers. Key to the efficient progress in this field is a clear understanding of the complex biology of the early stages of cancerization that proceed on the epithelial surface. Systematic analysis of the biology of strategic targets such as growth factors is one approach to this problem. Gastrin‐releasing peptide is an autocrine growth factor for certain types of lung cancer cells. Mechanisms involved in the production and activation of this peptide are discussed as an example of how rational approaches to neutralization of cancer promotion biology can be achieved. The tools to monitor the success of this type of intervention also emerge from the understanding of the biology of growth factors, and intermediate end point markers that determine the presence or effects of a growth factor are attractive candidates for evaluation. Additional biologic tools reflecting the early stages of the cancer process need to be validated for use in serially evaluating the status of the relevant epithelium so that the ongoing success of a cancer intervention procedure can be established. Through this type of translational research, important applications of molecular biology may greatly improve the success of preventative strategies for cancer control.

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