Tumor specimens of non-small cell lung carcinomas (NSCLC) from previously untreated patients (n = 153) were analysed immunohistochemically for expression of vascular endothelial growth factor (VEGF), ...VEGF-receptor (Flt-1), basic fibroblast growth factor (bFGF) and FGF-receptor (FGFR-1, (Flg). Expression of the proteins was compared with the in vitro response of the tumors against doxorubicin. The data clearly demonstrate that a significant relationship exists between VEGF (p < 0.001) and Flt-1 expression (p < 0.01) and drug response. The expression of VEGF and Flt-1 was lower in resistant than in sensitive tumors. In contrast, no significant interrelationship was found between expression of bFGF and response to doxorubicin. However, there exists a significant correlation between the expression of FGF-receptor (FGFR-1) and the response of the carcinomas to doxorubicin (p < 0.05). Expression of FGFR-1 was more frequently negative or weak in resistant and more frequently moderate or high in sensitive NSCLC. The data from this investigation clearly demonstrate that a significant interrelationship exists between the expression of VEGF, VEGF-receptor Flt-1 and FGF-receptor, FGFR-1 and the response of NSCLC to doxorubicin in vitro.
Doxorubicin- (OAW-dox, SK-OV-dox), taxol- (OAW-tax, SK-OV-tax) and cisplatin- (SK-OV-cis) resistant cells derived from the parental OAW-42 and SK-OV-3 cell lines were established. OAW-42 sublines ...showed high resistance, the SK-OV-3 sublines only low resistance. OAW-42 sublines showed a cross-resistance profile typical of multidrug resistance (MDR). The sublines of SK-OV-3 showed a cross-resistance profile different from the OAW-42 sublines. The mRNA expression of several resistance proteins and related factors was analyzed. An overexpression of P-glycoprotein 170 (P-170), glutathione-S-transferase-pi (GST-pi), thymidylate synthase (TS), glutathione peroxidase (GP) and c-jun was found in OAW-dox and OAW-tax cells. Additionally, OAW-tax cells expressed a higher mRNA level of protein kinase Cbeta2. DNA analysis revealed a 2-fold gene amplification of P-170, whereas the genes for GST-pi, TS and GP were not amplified. SK-OV-dox and SK-OV-tax cells showed a decreased level of histone 3 (H3) and TS mRNA. This shows that the sublines of OAW-42 developed resistance by co-expression of several resistance-related proteins and proto-oncogenes whereas the sublines of SK-OV-3 expressed resistance by decreased expression of the proliferation-dependent proteins H3 and TS.
In a retrospective analysis, acute lymphoblastic leukaemia (ALL) blast cells of 102 children were investigated for the expression of the retinoblastoma susceptibility (RB)-1 gene at mRNA level by dot ...blot hybridization and semiquantitative RT-PCR. 56 patients were analysed by dot blot hybridization and 35 representative patients out of this group by semiquantitative RT-PCR. Two additional groups of patients (23 patients with initial and 23 patients with relapsed ALL) were also investigated by semiquantitative RT-PCR. RB-1 gene expression was detectable in all investigated ALL at different levels. According to the relative mRNA expression the patients were discriminated by the median value in groups with low or high RB-1 expression. The Kaplan-Meier estimates showed that patients with low RB-1 expression had a lower probability of remaining in first remission (P = 0.03) and a significantly higher risk to succumb to their disease (P = 0.03). Furthermore, the comparison of the results between initial and relapsed ALL showed that the relapses had significantly lower RB-1 mRNA expression (P = 0.02). The overall survival of the patients was shorter in both groups when RB-1 gene expression was low. A multivariate analysis, including age, sex, immunological subtype, initial white blood cell count and RB-1 expression, identified RB-1 as an independent prognostic predictor (P = 0.017) in addition to the initial white blood cell count (P = 0.00001). In conclusion, low RB-1 expression is an unfavourable prognostic predictor in initial and relapsed childhood ALL. The RB-1 gene expression in relapsed ALL is significantly lower than in initial ALL.
In this report we review current studies concerning the RB-1 gene expression in acute leukemias. The RB-1 gene was analyzed in several studies by protein-, RNA and DNA-techniques in acute ...lymphoblastic leukemia (ALL) as well as in acute myelogenous leukemia (AML). The frequency of RB-1 inactivation in ALL-patients ranged between 30% and 64% in several studies. Structural abnormalities of the RB-1 gene were reported in 18% of ALL-patients and in 27% of Philadelphia chromosome-positive ALL, respectively. The proportion of AML-patients with absent RB-1 protein expression ranged between 19% and 55%. Structural RB-1-abnormalities in AML were predominantly reported in leukemias with monocytic differentiation. Furthermore, the prognostic value of an abnormal RB-1 gene expression was also estimated in some studies. In childhood ALL RB-1 inactivation was reported to have prognostic significance while in contrast, in another study on adults no prognostic value of RB-1 was found. In 4 out of 5 documented studies AML-patients with RB-1 inactivation generally had a poorer prognosis. In conclusion, RB-1 inactivation is frequently observed in acute leukemia. The prognostic value of low RB-1 expression is controversial but the majority of published studies found low RB-1 expression to be a negative prognostic predictor, in acute leukemia.
