A phase-ii trial of 5-Fluorouracil, folinic Acid, vinorelbine in pretreated patients with metastic colorectal-cancer.

43 patients with metastatic colorectal Cancer pretreated with 5-fluorouracil-based chemotherapy received vinorelbine plus 5-fluorouracil plus folinic acid with the aim of evaluating vinorelbine activity in advanced colorectal cancer and its potential synergism with commonly used drugs. 9 partial responses were observed, for an;overall objective response rate of 20.9%. 20 additional patients had stable disease (46.5%). Median duration of response was 7 months. Median survival from the start of treatment was 6 months. The main toxic effect was myelosuppression. We conclude that our regimen is active enough to warrant further evaluation in advanced colorectal cancer.

Treatment of advanced non-small cell lung cancer with very high-dose cisplatin combined with etoposide and mitomycin C.

BACKGROUND: Treatment options for advanced non-small-cell lung cancer are inadequate. There remains a critical need for more effective systemic therapies. METHODS: Forty-one patients with advanced non-small-cell lung cancer were treated on a 28-day cycle with a very high-dose, cisplatin-based three-drug regimen. A treatment cycle consisted of an intravenous (IV) injection of cisplatin 100 mg/m2 on days 1 and 8; etoposide 60 mg/m2 IV over 30 minutes on days 1, 2, 8, and 9 (cycles 1 and 3 only); and mitomycin C 8 mg/m2 IV bolus on day 1 (cycles 2 and 4 only) (PEM regimen). RESULTS: The median dose intensity of cisplatin delivered was 49 mg/m2/wk, or 98% of the planned dose. One patient achieved a complete response and 16 patients a partial response or regression, yielding an overall objective response rate of 41%. The median duration of response was 21 weeks. Median survival of all patients was 38 weeks. Neurologic toxicity was dose limiting. The frequency of peripheral neuropathy and ototoxicity was directly related to cumulative cisplatin dose. In five patients, a progressive peripheral neuropathy developed after discontinuation of cisplatin. Hematologic toxicity also was significant. CONCLUSIONS: This very high-dose, cisplatin-based chemotherapy regimen has appreciable activity in advanced non-small-cell lung cancer. In comparison with previous reports on the use of very high-dose cisplatin alone, however, this combination appears at best to be only marginally more active, to confer no additional survival advantage, and to be considerably more toxic.

Minisatellite allele diversification: the origin of rare alleles at the HRAS1 locus.

Three genetic markers within the promoter-exon 1 region of the HRAS1 locus have been employed to investigate lineage relationships among alleles of the highly polymorphic variable tandem repeat (VTR) immediately downstream of the HRAS1 gene. These markers were in absolute linkage disequilibrium with the HRAS1 VTR, allowing the assignment of unique upstream haplotypes to each of the four common VTR alleles. Analysis of 17 rare alleles revealed a stratification of allele fragment size and upstream haplotype in which each rare VTR allele possessed the markers characteristic of the common allele nearest in size. Therefore, hyperallelism emanated from the four common alleles in a defined fashion, the size of a rare allele specifying its origin. As discussed below, this result implies that unequal crossing-over between homologues is unlikely to be the predominant mechanism for generating new VTR alleles at this minisatellite locus.

Human hypervariable sequences in risk assessment: rare Ha-ras alleles in cancer patients.

A variable tandem repeat (VTR) is responsible for the hyperallelism one kilobase 3' to the human c-Ha-ras-1 (Ha-ras) gene. Thirty-two distinct restriction fragments, comprising 3 allelic classes by frequency of occurrence, have thus far been detected in a sample size of approximately 800 caucasians. Rare Ha-ras alleles, 21 in all, are almost exclusively confined to the genomes of cancer patients (p less than 0.001). From our data we have computed the relative cancer risk associated with possession of a rare Ha-ras allele to be 27. To understand the molecular basis for this phenomenon, we have begun to clone Ha-ras fragments from nontumor DNA of cancer patients. We report here the weak activation, as detected by transfection and transformation of NIH 3T3 mouse cells, of two Ha-ras genes which were obtained from lymphocyte DNA of a melanoma patient. We have mapped the regions that confer this transforming activity to the fragment containing the VTR in one Ha-ras clone and the fragment containing gene coding sequences in the other.

Human restriction fragment length polymorphisms and cancer risk assessment.

The polymorphic restriction fragments of the human Ha-ras locus, produced by the variable tandem repetition (VTR) of a short consensus sequence, fall into three classes based on allelic frequencies. Alleles of the "rare" class (individual frequencies less than 0.5%) have been detected only in white blood cell and tumor DNA of cancer patients. This phenomenon is independent of ethnic origin. No significant association of rare alleles with cancer patients has been demonstrated at an independent tandem repeat locus, VTR4.1. The results suggest that the Ha-ras restriction fragment length polymorphism is useful in cancer risk assessment.

Unique allelic restriction fragments of the human Ha-ras locus in leukocyte and tumour DNAs of cancer patients.

White blood cell DNA from cancer patients and DNA from tumours and tumour-derived cell lines frequently demonstrated allelic restriction fragments of the Harvey ras oncogene locus not found in the unaffected population. The presence of such unusual alleles may be linked to susceptibility to cancer.

17 beta-hydroxysteroid dehydrogenase deficiency in malignant interstitial cell carcinoma of the testis.

A partial defect in testosterone (T) secretion due to a 17 beta-hydroxysteroid dehydrogenase deficiency has been documented in a patient with advanced metastatic interstitial cell carcinoma of the testis. Basal serum T was decreased (83 ng/ml), whereas androstenedione was markedly elevated (847 ng/ml). Dehydroepiandrosterone sulfate and estrone were moderately increased, while LH, FSH, and estradiol were minimally increased. After hCG administration, androstenedione rose to much greater degree than T. Fluoxymesterone failed to suppress circulating androgens and estrogens to below basal values, although LH and FSH were suppressed to immeasurable levels. These data support a partial enzyme deficiency within the tumor. They also suggest that although the tumor was autonomous, it still was capable of being stimulated by exogenous gonadotropins.