Mechanisms Of Treatment Failure Research Articles

Tumor metastasis inhibition with the prostacyclin analogue cicaprost depends on discontinuous plasma peak levels

Stable prostacyclin analogues exert a strong inhibitory effect on lymphogenous as well as haematogenous tumor metastasis in a series of tumor lines. The strong inhibition of metastasis was achieved by repeated once-daily i.g. applications. The mechanism of antimetastatic action is related to the expression of functional IP-receptors (PGI-receptors). As cellular assay systems indicated that the IP-receptor mediated signalling is down-regulated upon continuous exposure to prostacyclin or stable derivatives, it has been questioned whether a mode of drug application with constant plasma drug levels may potentially result in a decrease of the antimetastatic effect. We addressed this question using the stable prostacyclin analogue cicaprost in a disease model by comparing i.g. applications given once daily with a continuous administration of equivalent doses via drinking water. Very similar to our previous investigations in the 13762NF MTLn3 rat mammary carcinoma model, cicaprost administered by i.g. application strongly reduced lung and lymph node metastasis. In contrast, administration of equivalent doses via drinking water leading to lower but constant steady-state plasma levels failed to exert inhibitory effects. Plasma and urine levels of cicaprost were measured with a sensitive radioimmunoassay on the last treatment day. Pharmacokinetic evaluation demonstrated a similar bioavailability of cicaprost in both groups. This result first demonstrates a treatment failure of a prostacyclin derivative in a chronic disease model in association with a continuous drug administration leading to constant plasma levels. A desensitization of receptor signalling by constant plasma levels may be a possible mechanism for treatment failure.

Mechanisms of treatment failure.

The recently published overview of systemic treatment of patients with early breast cancer provides the best information available concerning the impact of these treatments on disease-free and overall survival [4] (reprinted in part in this volume). The modest reduction in risk of relapse achieved by these treatments may translate into major community health benefits when viewed in the context of a common disease affecting hundreds of thousands of women in the world each year. However, these results also indicate that many women who have received adjuvant systemic treatments die of metastatic breast cancer, presumably because some cells in the micrometastatic disease present before treatment survive after adjuvant treatment is ceased, and these cells later grow to cause advanced disease and premature death. Strategies to improve these results must include, on the one hand, the development of techniques to identify women with early breast cancer who have a normal life expectancy without adjuvant systemic therapy, i.e., either no metastases or metastases which will not cause symptoms during life, and, on the other, to establish the therapy which eliminates micrometastases or prevents their growth.

Depolarization blockade in denervated hippocampus: A possible mechanism for treatment failure in Alzheimer's disease

Depolarization blockade in denervated hippocampus: A possible mechanism for treatment failure in Alzheimer's disease

Levels of Keratan Sulfate-Bearing Fragments Rise Predictably following Chemonucleolysis of Dog Intervertebral Discs with Chymopapain

Chymopapain (1 mg) was injected into each of four-lumbar intervertebral discs of adult mongrel dogs. As expected, at 2 weeks, all injected discs exhibited marked loss of height (mean: 50% of original height) indicative of severe proteoglycan depletion. The appearance of keratan sulfate-bearing fragments in plasma was monitored by an ELISA-inhibition assay which uses a monoclonal antibody (1/20/5-D-4) specific for an epitope present only in the longest keratan sulfate chains. Levels of plasma keratan sulfate rose within 30 minutes and reached a maximum between 24 and 72 hours later. Levels then declined progressively but were still elevated at 2 weeks postinjection. Keratan sulfate-bearing fragments in plasma were purified by ion exchange chromatography on DEAE-Sephacryl and fractionated by sieve chromatography on Sepharose CL-6B. These plasma keratan sulfate-bearing fragments were found to be similar in size to keratan sulfate-bearing fragments generated by chymopapain digestion of dog nucleus pulposus proteoglycans, but slightly larger than single keratan sulfate chains obtained by alkaline borohydride treatment of dog nucleus pulposus proteoglycans. The results of this study show that measurements of blood levels of keratan sulfate could prove useful in monitoring effective degradation of disc proteoglycans in chemonucleolysis in man and help discriminate between ineffective enzyme placement, and alternative mechanisms of treatment failure.

Clinical studies with adjunctive surgery and irradiation therapy in the treatment of carcinoma of the cervix.

The majority of patients with cancer of the cervix are treated adequately by irradiation alone, and surgery is not necessary. A role for operation developsin certain patients with Stage I-II cancer of the cervix, who are prone to develop central recurrence if treated by irradiation alone. In these patients the primary lesion is massive. The vasculature to the center of these bulky or barrel-shaped cancer is insufficient, and a population of the cancer cells, perhaps related to anoxia, is more resistant to irradiation. The postirradiation conservative hysterectomy was incorporated into the treatment plan for 212 selected patients and the number of local recurrences was reduced. Incomplete cure of the peripheral component of the disease is another mechanism of treatment failure. This may occur, even though the primary lesion is cured. Patients with cervical cancers greater than 5 cm diameter have a high incidence of node metastasis, regardless of clinical stage. In those patients with positive nodes, the standard portals for external irradiation were expanded to include nodes at higher levels. The site of metastases was established by pretreatment laparotomy and the irradiation portals were then extended to include the involved nodes. Survival rates were not improved, because recurrences were not prevented, and death from treatment complications were high.