Encapsulation of teniposide into albumin nanoparticles with greatly lowered toxicity and enhanced antitumor activity.

Teniposide (VM-26) is a semisynthetic derivative of podophyllotoxin effective for the treatment of many types of tumors. However, the poor water solubility and adverse effects restrict its clinical use. Our study aimed to develop a novel phospholipid complex albumin nanoparticle (VM-E80-AN) to reduce the systemic toxicity and enhance antitumor activity of VM-26. Egg yolk lecithin E80 and human serum albumin (HSA) were used as the main excipients to replace Cremophor EL in the commercial formulation. The physicochemical properties of VM-E80-AN were characterized to optimize the formulation. Cell and animal studies were further carried out to estimate its tumor inhibition efficacy, biodistribution, and toxicity. Comparison between VM-26 solution and VM-E80-AN showed that VM-E80-AN significantly reduced the toxicity of VM-26 and enhanced the anticancer efficacy of the drug. Thus, VM-E80-AN represents a safe and promising formulation of teniposide for clinical application.

Use of a rapid throughput in vivo screen to investigate inhibitors of eukaryotic topoisomerase II enzymes.

Topoisomerase II catalyzes the passage of one DNA helix through another via a transient double-stranded break. The essential nature of this enzyme in cell proliferation and its mechanism of action make it an ideal target for cytotoxic agents. Saccharomyces cerevisiae topoisomerase II has been frequently used as a model for testing potential inhibitors of eukaryotic topoisomerase II as antitumor agents. The standard in vivo method of estimating the sensitivity of S. cerevisiae to the antitopoisomerase drugs is via inhibition or kill curves which rely on viable-cell counts and is labor intensive. We present an alternative to this, a high-throughput in vivo screen. This method makes use of a drug-permeable S. cerevisiae strain lacking endogenous topoisomerase II, which is modified to express either human topoisomerase IIalpha or IIbeta or S. cerevisiae topoisomerase II carried on plasmids. Each modified strain expresses a full-length topoisomerase II enzyme, as opposed to the more commonly used temperature-sensitive S. cerevisiae mutant expressing yeast or yeast/human hybrid enzymes. A comparison of this new method with a plating-and-counting method gave similar drug sensitivity results, with increased accuracy and reduced manual input for the new method. The information generated has highlighted the sensitivities of different topoisomerase II enzymes and isoenzymes to several different classes of topoisomerase II inhibitor.

Teniposide in adult solid tumors: a historical perspective.

Teniposide and etoposide are third-generation semi-synthetic derivatives of epipodophyllotoxin. Following the initial clinical introduction of teniposide in the 1970s, investigations focused almost exclusively on its analogue, etoposide, because of its formulation, which was felt to have advantages in addition to oral administration. Despite consistently inadequate dosing and scheduling, early phase I and II trial results with teniposide were promising, and current trends encourage a second look. The substantial antitumor activity of teniposide is comparable with that of etoposide, and clinical interest was rekindled when it was shown to have considerable activity against small cell lung cancer (SCLC). In view of the inadequacy of early trials and the premature cessation of clinical study, it is recommended that teniposide be reevaluated for its activity against malignant lymphomas, Hodgkin's disease, leukemias, and SCLC, against all of which its early results were encouraging. In addition, consideration should be given to its activity against brain tumors, neuroblastomas and other childhood solid tumors, and ovarian cancer; its potential value against gastric, hepatocellular, breast, and bladder cancers also should be investigated. Other areas that warrant further study include elucidation of the exact mechanism of action of teniposide, its role in both single- and multiple-agent chemotherapeutic regimens, and resolution of its optimal dose and schedule. Finally, it is suggested that with new routes of administration and improved formulations, teniposide may be expected to play a significant role in the treatment of malignant lymphomas, SCLC, and pediatric lymphocytic leukemia and neuroblastoma.

Vidarabin-monophosphate, BCNU, VM26--an in vitro comparative study of active agents in the treatment of malignant human brain tumours.

BCNU (carmustine), VM26 (teniposide) and ARA-A5'P (vidarabin-monophosphate) were compared in their activity against 30 cell lines of primary (N = 21) and metastatic (N = 9) human brain tumours, which were characterized in tissue culture by cytochemical, immunological and cytogenetic criteria. In vivo achievable concentration-time products c X t were correlated with in vitro pharmacokinetic data in order to evaluate in vitro drug sensitivity at relevant exposure doses. A microcytotoxicity assay was employed to screen for drug toxicity in individual tumour cell lines. Following drug exposure and 5 to 8 population doubling times of untreated controls, RNA-synthesis - as a parameter of cell metabolism and proliferation - was determined by incorporation of [5,6-3H]-uridine into cellular RNA (liquid scintillation counting protocol). The cytotoxic effect of each drug on individual cell lines was expressed in terms of a sensitivity index (SI); by these means effects of different drugs on individual tumour cell lines could be compared. Mean sensitivity indices of ARA-A5'P, BCNU and VM26 for primary brain tumour cell lines were 0.59, 0.82 and 0.54. ARA-A5'P and VM26 had almost similar activities against brain tumour cell lines, whereas BCNU was significantly (P less than 0.001) less active. High grade gliomas were less sensitive to all three agents than low grade and infratentorial gliomas. ARA-A5'P was also able to effectively reduce colony formation in brain tumour cell lines. A cross-resistance of ARA-A5'P to either BCNU or VM26 could not be observed. Clearly, ARA-A5'P is an effective drug in treatment of brain tumour cells in vitro.

Activity and pharmacokinetics of teniposide in Lewis lung carcinoma-bearing mice.

The antitumor activity of teniposide (VM26) was investigated in Lewis lung carcinoma (3LL) of the mouse after a single dose of 20 mg/kg iv (given 8 or 14 days after tumor transplant) or after three doses of 6.5 mg/kg iv (given on Days 8, 11, and 14 after tumor transplant) (total dose, 19.5 mg/kg). The single dose resulted in only 25% primary tumor reduction but had marked antimetastatic activity. The repeated doses (6.5 mg/kg x 3) were much more effective, with 85% primary tumor reduction and the apparent disappearance of all metastatic deposits. The pharmacokinetics of VM26 was investigated in 3LL-bearing mice by a high-performance liquid chromatographic assay. At both of the above doses VM26 disappeared from mouse plasma biphasically, with an elimination half-life of about 70 mins. The concentrations in metastases were higher than in primary tumor, where very low levels were found. The highest VM26 levels were found in liver, small intestine, and kidney, and the lowest levels were found in the brain. Excretion of VM26 in urine amounted to less than 5% of the dose.