homoharringtonine and Colonic-Neoplasms

Anorexia-cachexia syndrome (ACS) is a major determinant of cancer-related death that causes progressive body weight loss due to depletion of skeletal muscle mass and body fat. Here, we report the development of a novel preclinical murine model of ACS in which lymphomas harbor elevated Myc and activated mTOR signaling. The ACS phenotype in this model correlated with deregulated expression of a number of cytokines, including elevated levels of interleukin-10 which was under the direct translational control of mTOR. Notably, pharmacologic intervention to impair protein synthesis restored cytokine production to near-normal levels, delayed ACS progression, and extended host survival. Together, our findings suggest a new paradigm to treat ACS by strategies which target protein synthesis to block the production of procachexic factors.

Topics: Animals; Anorexia; Antineoplastic Agents; Body Weight; Cachexia; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Female; Harringtonines; Homoharringtonine; Humans; Interleukin-10; Kaplan-Meier Estimate; Lymphoma; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Protein Biosynthesis; Proto-Oncogene Proteins c-myc; Signal Transduction; Sirolimus; Syndrome; TOR Serine-Threonine Kinases

To make full use of cephalotaxus plant resources and search for antitumor agents with higher activities and lower side effects.. The C3 hydroxy groups of the cephlotaxine and drupacine were acylated by taxol side chain and its isomers to give a series of derivatives of cephlotaxine and drupacine.. Six novel alkaloid esters were designed and synthesized. The pharmacological screening results showed that VIIIa, VIIIb, IXa and IXc exhibited significant activities on KB, HCT and Bel in vitro.. Novel alkaloid esters are worthy to be intensively studied.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Colonic Neoplasms; Harringtonines; Homoharringtonine; Humans; KB Cells; Liver Neoplasms; Tumor Cells, Cultured

Homoharringtonine (HHT) is a new drug with antileukemic activity which is currently tested for treatment of acute and chronic leukemias, either alone or in combination with other agents. Since HHT showed a low efficacy in refractory and relapsed acute leukemia and in the blastic phase of chronic myeloid leukemia (CML) which are frequently characterized by an overexpresion of the multidrug resistance (MDR)-related P170-glycoprotein, we postulated a relationship between the poor antileukemic effect of HHT in these leukemias and the expression of P170-glycoprotein. For this reason, sensitive (LOVO109 and CEM) and MDR (LOVO DX and CEM VLB) cell lines were exposed to HHT with or without some MDR modifiers, namely, Cyclosporine A (CyA), the Cyclosporine derivative SDZ PSC 833 (PSC), and the D-isomer of Verapamil (DVRP). It was found that MDR cells were about 15 times more resistant to HHT than non-MDR cells, and that resistance to HHT was significantly decreased by all the MDR modifiers that were tested. This in vitro study showed that HHT belongs to the category of MDR-related drugs, like anthracyclines, vinca alkaloids, epipodophylline derivatives, and taxol.

Topics: Adenocarcinoma; ATP Binding Cassette Transporter, Subfamily B, Member 1; Colonic Neoplasms; Cyclosporins; Daunorubicin; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Gene Amplification; Harringtonines; Homoharringtonine; Humans; Leukemia-Lymphoma, Adult T-Cell; Neoplasm Proteins; Tumor Cells, Cultured; Verapamil; Vinblastine

Human colon (HCT116/VP48) and lung (A549B/VP29) adenocarcinoma cell lines selected for resistance to etoposide exhibited modified patterns of multi-drug resistance (MDR) that included a differential sensitivity to other DNA topoisomerase II inhibitors and to the plant alkaloids homoharringtonine, vinblastine, and vincristine. The resistance and cross-resistance drug phenotype of the A549B/VP29 cell line was different from that of the HCT116/VP48 cell line. The HCT116/VP48 cell line was 50-fold resistant to etoposide and 30-fold resistant to teniposide. The degree of resistance to other DNA topoisomerase II inhibitors was of a lower magnitude: Adriamycin, 9-fold; daunomycin, 3-fold; 4'-[(9-acridinyl)-amino]-methanesulfone-m-anisidide (m-AMSA), 3-fold; and actinomycin D, 6-fold. The HCT 116/VP48 cell line exhibited a 7-fold resistance to vincristine and a 2-fold resistance to vinblastine but was sensitive to homo-harringtonine. The A549B/VP29 cell line was 5-fold resistant to etoposide and 2-fold resistant to teniposide. The A549B/VP29 cell line exhibited a 2-fold resistance to Adriamycin but was sensitive to daunomycin and showed a 3-fold resistance to m-AMSA. This cell line was sensitive to actinomycin D. The A549B/VP29 cell line was 2-fold resistant to vinblastine and sensitive to homoharringtonine. Both cell lines (HCT116/VP48 and A549/VP29) exhibited no amplification of the human mdr1 DNA sequence, the 4.3-kb P-glycoprotein transcript, or the membrane P-glycoprotein. The sensitivity of cells exhibiting an MDR phenotype not mediated by P-glycoprotein suggests a potential use for homoharringtonine in treating tumors with this type of drug resistance.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Colonic Neoplasms; Drug Resistance; Etoposide; Harringtonines; Homoharringtonine; Humans; Lung Neoplasms; Tumor Cells, Cultured

We investigated the effects of combined treatment with homoharringtonine (HHT) and hyperthermia on cytotoxicity and transcriptional regulation of heat shock genes in human colon carcinoma (HT-29) cells. The drug (100 ng/ml) which inhibited protein synthesis by 93% protected cells from killing at 43 degrees C. For example, treatment with HHT 2 hr before and during heating produced a 9-fold increase in survival from 3.7 x 10(-2) to 3.2 x 10(-1) after 10 hr at 43 degrees C. Little or no protection was observed if the drug was added only during heating. Interestingly, adding the drug (100 ng/ml) 2 hr before and during heat facilitated the dissociation of heat shock transcription factor-heat shock element (HSF-HSE) complex during continuous heating at 43 degrees C. These findings related to the literature suggest that the free pool of HSC70 is increased by inhibiting protein synthesis. An increase in the level of free HSC70 may more effectively protect or repair thermolabile targets and consequently affect regulation of heat shock response.

Topics: Antineoplastic Agents, Phytogenic; Base Sequence; Carrier Proteins; Cell Line; Cell Survival; Colonic Neoplasms; DNA-Binding Proteins; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Harringtonines; Heat Shock Transcription Factors; Heat-Shock Proteins; Homoharringtonine; Hot Temperature; HSC70 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Kinetics; Molecular Sequence Data; Oligodeoxyribonucleotides; Promoter Regions, Genetic; Transcription Factors; Transcription, Genetic; Tumor Cells, Cultured

Advanced subcutaneous Colon 38 tumours in mice were used for the assessment of activity of a number of anticancer drugs. Activity was measured by histological examination of tumours 24 h after a single dose of the drug and in some cases by tumour growth delay. Agents thought to exert their cytotoxic effect by damaging DNA, including Adriamycin, amsacrine and its analogue CI-921, cyclophosphamide, 5-fluorouracil and methotrexate produced no gross histological changes after 24 h, even though some delayed the growth of subcutaneous tumours. In contrast, flavone acetic acid, fostriecin and homoharringtonine caused extensive necrosis of tumours after 24 h, and each delayed the growth of advanced subcutaneous tumours by at least 10 days when administered as a single dose. The histological effects of flavone acetic acid and fostriecin were indistinguishable from those of recombinant human tumour necrosis factor alpha. It is proposed that histological assay of advanced tumours may provide a useful adjunct to existing methods in screening for antitumour agents with novel mechanisms of action.

Topics: Alkaloids; Alkenes; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Colonic Neoplasms; Drug Screening Assays, Antitumor; Flavonoids; Harringtonines; Homoharringtonine; Mice; Mice, Inbred Strains; Polyenes; Pyrones; Tumor Necrosis Factor-alpha

Five phase II trials of the antitumor agent homoharringtonine were conducted in 80 patients who had advanced solid tumors. The five categories of solid tumors included malignant melanoma; sarcoma; and head and neck, breast, and colorectal carcinomas. The starting dose of homoharringtonine was 3.0-4.0 mg/m2 by short iv infusion daily X 5 days every 21 days. Seventy-eight of 80 patients had had prior chemotherapy and 49 had had prior radiation therapy. Among the 74 evaluable patients in the five tumor categories, there were no complete or partial remissions. Homoharringtonine was generally well-tolerated. Nausea and vomiting, diarrhea, and fever and chills were the most common side effects. Serious reversible cardiovascular toxicity, which occurred in three patients, included symptomatic hypotension in two and short runs of ventricular tachycardia in one. The investigations thus conclude that homoharringtonine given by intermittent schedule is an inactive drug against these solid tumors previously exposed to chemotherapy.

Topics: Adolescent; Adult; Aged; Alkaloids; Bone Marrow; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Drug Evaluation; Female; Harringtonines; Head and Neck Neoplasms; Heart; Homoharringtonine; Humans; Hypotension; Male; Melanoma; Middle Aged; Rectal Neoplasms; Sarcoma