LU103793 (NSC D-669356): a synthetic peptide that interacts with microtubules and inhibits mitosis.

LU103793 (NSC D-669356) is a new synthetic derivative of Dolastatin 15, an antiproliferative compound which was isolated from the mollusk Dolabella auricularia. Like Dolastatin 15, LU103793 is highly cytotoxic in vitro (IC50 = 0.1 nM). To investigate the mechanism of action of LU103793, we used a combination of biochemical and cellular methods. Turbidity assays with bovine brain microtubules demonstrated that LU103793 inhibits microtubule polymerization in a concentration-dependent manner (IC50 = 7 microM). Treatment with this compound also induced depolymerization of preassembled microtubules. Cell cycle analysis of tumor cell lines treated with LU103793 indicated a block in the G2-M phase. At the cellular level, it induced depolymerization of microtubules in interphase cells and development of abnormal spindles and chromosome distribution in mitotic cells. Although these effects are very similar to the cellular alterations caused by vinblastine, LU103793 does not inhibit vinblastine binding to unpolymerized tubulin in vitro. Our results suggest that LU103793 exerts its cytotoxic activity primarily through disruption of microtubule organization.

Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity.

LU 79553 is a novel bis-naphthalimide which is highly cytotoxic in vitro with EC50 (concentration required for 50% inhibition of growth) ranging from 2 x 10(-7) to 5 x 10(-10) M. A number of studies were conducted to examine its antitumor activity in human xenograft models. In addition, we wanted to explore the possible schedule dependency of LU 79553 cytotoxicity in these xenograft models. Complete regression of MX-1 (mammary carcinoma) xenografts was observed when LU 79553 was administered i.v. daily for 5 doses at 20 mg/kg (2 cycles starting on Days 6 and 20) or every 3 days for 2 doses at 55 mg/kg (2 cycles starting on Days 6 and 13) or every 7 days for 4 doses. Complete regression was also seen in the MX-1 model when tumors were staged at 1-2 g prior to the initiation of treatment. Regressions (complete or partial) were observed in the LX-1 (lung), CX-1 (colon), DLD (colon), and LOX (melanoma) xenograft models. A significant increase in the median survival time of OVCAR-3- (ovarian carcinoma) bearing mice was noted in LU 79553-treated animals (treated/control = 195%). The excellent activity of this compound in such a wide variety of tumor types suggests LU 79553 merits further investigation in clinical trials.

Ras gene activation and epidermal growth factor receptor expression in human colon cancer.

The expression of various epitopes of epidermal growth factor receptor (EGFr) and mutational activations of ras gene product p21 in colorectal primary cancers from 16 patients have been analyzed in this study. Eight noncancerous colons were used as controls. Indirect immunoperoxidase staining was performed using Avidin-Biotin Complex assay. Monoclonal antibodies against carbohydrate and polypeptide epitopes of EGFr and monoclonal antibodies against "wild-type" and "mutant" ras p21 were used as specific probes. There was no specific expression of the polypeptide epitope of EGFr observed in any of the colon cancers or normal colon tissues. Four of the sixteen tumors (25%) expressed the carbohydrate epitope of EGFr. Glycine----arginine mutation and glycine----valine mutation of codon 12 in ras p21 was observed in 40 and 31% of colon cancers, respectively. Although normal colon showed expression of wild-type ras in about half the cases studied, there was no mutational activation of the ras genes. The morphologically adjacent normal colon mucosa in cancer patients expressed varying levels of mutational activation involving the codon 12. The presence of unusual carbohydrates relating to the EGFr and the products of ras gene activation by point mutations in colon cancers may imply a functional role in transformation.

Relationship of neurological and psychological signs to physical and metabolic risk factors in elderly persons living in retirement facilities: a multidisciplinary approach.

A multidisciplinary study was performed on 128 elderly subjects living in retirement facilities to correlate the occurrence of neurological signs with the presence of physical or metabolic risk factors, and cognitive impairment. Primitive reflexes were significantly correlated with ankle/arm ratio, Hachinski dementia score, Plutchik GRS score, and hypomimia. The contemporary presence of snout reflex, glabella tap, and palmomental reflex was consistently associated with dementia.

Experimental liver metastasis. Implications of clonal proclivity and organ specificity.

"Spontaneous" lung metastases develop in over 50% of the animals bearing subcutaneous isografts of WB-2054, a rat colon carcinoma. A metastatic variant has been developed by "Fidler" type in vivo selection, yielding 100% lung metastasis. In a five-week assay to test the organ specificity of this lung metastatic variant, however, "experimental" liver and lung metastases could be induced in 100% and 60% of animals on portal venous and intravenous injections, respectively. The results demonstrate selection of a metastatic variant from heterogeneous primary tumor, and suggest at least two interacting mechanisms: (1) mechanical (the anatomy of the blood-borne metastatic pathways) and (2) biologic (factors intrinsic to primary tumor subpopulations that can be selected for metastatic proclivity). In addition, liver metastases were successfully established from colon tumors induced by cecal wall injection of tumor cells. Such a spontaneous liver metastasis model will be useful to study the specific mechanisms involved during metastasis of colon cancer to the liver.

Verbal and spatial memory span in patients with extrapyramidal diseases.

Spatial span (Corsi's block-tapping test) and verbal span (Wechsler's Digits Forward test) were measured in 651 normal subjects and in three groups of extrapyramidal patients (Progressive supranuclear palsy, Parkinson, and Huntington's Chorea). Analysis showed Huntington's Chorea patients scored lower on both tests than did controls and other groups.

Effects of age, education and sex on two tests of immediate memory: a study of normal subjects from 20 to 99 years of age.

Spatial span (Corsi's block-tapping test) and verbal span (Wechsler Digits Forward) were measured in 1354 normal subjects, aged from 20 to 99 yr., who were subdivided into seven age groups, into three groups according to education, and according to sex. Analysis of variance showed that the three main factors were significant for the spatial span test. The two spans examined held well up to the 60s, and only after this age did significant differences appear in the other age groups. On both tests there were significant differences between the groups divided according to education.