To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.

SUMMARY:Certain drugs used in the treatment of lung cancer and other human malignancies are cytotoxic because of their ability to interact with the two isoforms of topoisomerase II (topo II), topo II␣ and topo II␤. As part of an effort to evaluate the contribution of topo II alterations to drug sensitivity and resistance in lung cancer, we have developed a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay to measure levels of topo II ␣ and ␤ mRNAs simultaneously using a single pair of primers with sequences common to both isoforms. The PCR products derived from the topo II ␣ and ␤ mRNAs are both 446 bp but have different electrophoretic mobilities in a nondenaturing polyacrylamide gel, allowing sensitive, rapid quantitation when the products are radiolabeled with [ 35 S]-dATP. Using this RT-PCR method, poly(Aϩ) RNA from 13 non-small cell lung cancer (NSCLC) cell lines was analyzed. The results obtained indicated that the cell lines express a wide range of topo II␣ mRNA levels (12-fold) and topo II␤ mRNA levels (5.5-fold). Tumor and normal lung tissues from 25 patients with NSCLC were also examined. In the tumor samples, the levels of the topo II ␣ and ␤ mRNAs were similar. However, mean topo II␣ mRNA levels in the tumors were approximately 7-fold higher than those of the paired normal lung tissues. In contrast, topo II␤ mRNA levels were similar in both tumor and normal lung. Topo II ␣ and ␤ mRNA levels were both significantly lower in the squamous cell tumors than in the adenocarcinoma samples. Topo II␤ mRNA levels in the squamous cell tumors were also significantly lower than those in paired normal lung tissue. The RT-PCR method described is reliable and convenient, and for the first time, makes the rapid simultaneous direct comparison of topo II␣ and topo II␤ mRNA levels feasible in large numbers of clinical samples. (Lab Invest 2000, 80:787-795).T opoisomerase II (topo II) is a nuclear enzyme that alters the topology of DNA and is essential for normal chromosome segregation at mitosis. In mammalian cells, there are two isoforms, designated topo II␣ and topo II␤, which share more than 70% amino acid identity, but differ in their relative levels of expression in developing embryonic tissues, normal adult tissues, and tumors (Mirski and Cole, 1997). A number of clinically important anticancer drugs interact with topo II to produce DNA damage and cell death by apoptosis. Topo II poisons, such as and doxorubicin, stabilize an intermediate of the enzyme's catalytic cycle, the "cleaved complex" of topo II, DNA, and drug. Resistance to these topo II targeting drugs arises through a number of different mechanisms in human tumor cell lines, including decreased levels of the enzyme, mutations in the ATPase or DNA breakage and religation domains, or, in the case of the ␣ isoform, decreased nuclear localization (Larsen and Skladanowski, 1998;Mirski and Cole, 1997;Nitiss and Beck, 1996). A second class of topo II interactive drugs, which includes the investigational agents ICRF-187 and ICRF...