Treatment of androgen-independent prostate cancer using antimicrotubule agents docetaxel and estramustine in combination: an experimental study.

BACKGROUND: Estramustine in combination with other chemotherapeutic agents has demonstrated synergy in hormone-refractory prostate cancer. Docetaxel has demonstrated antineoplastic activity in a variety of chemotherapeutic-unresponsive tumors. We evaluated the effects of estramustine and docetaxel in preclinical models of prostate cancer. METHODS: Cell viability of PC-3 and MAT-LyLu (MLL) cells were assessed 48 hr after drug treatment. For in vivo studies, each flank of five animals in six groups was injected with 1 x 10(6) MLL cells: control, estramustine, docetaxel (low- and high-dose), and low- and high-dose docetaxel with estramustine. Animals were treated on days 4 and 11, and sacrificed on day 14. RESULTS: The IC(50) value for docetaxel was 2 nM in the PC-3 cells and 40 nM in the MLL cells. The addition of 100 nM of estramustine did not alter the IC(50) value for PC-3 cells. In the MLL cells, however, the IC(50) value was lowered to 15 nM. In vivo, low-dose docetaxel with estramustine demonstrated antineoplastic activity similar to that of high-dose docetaxel alone, suggesting additive activity between the drugs. CONCLUSIONS: These results demonstrate that when used in combination, docetaxel and estramustine can be more effective at lower dosages than when the individual drugs are used alone.

Etoposide in prostate cancer.

Hormone refractory prostate cancer is a disease that kills approximately 39,000 people per year. No single chemotherapeutic agent or regimen has been demonstrated to provide a survival advantage in this disease. Etoposide as a single agent, both in i.v. and oral formulations has not proven to be effective. In the 1990s, however, etoposide has been combined with several agents to create novel treatment regiments for patients with hormone refractory disease. Several of these regimens, all involving oral etoposide, have demonstrated promising results in Phase II trials and early results suggest that they may increase survival for hormone refractory patients, although this remains to be tested in a Phase III trial setting.

Novel molecular targets for prostate cancer therapy.

The treatment options available for advanced prostate cancer are increasing. These improved therapies are the result of research involving cellular targets other than DNA proliferation. For example, therapy directed against the intracellular matrix has yielded clinical responses in patients. Other novel targets are being investigated. This review examines both laboratory and clinical advances using cell structure, growth factors, differentiating agents, angiogenesis, metastasis, and the cell cycle in the treatment of prostate cancer.

Signaling network of paclitaxel-induced apoptosis in the LNCaP prostate cancer cell line.

OBJECTIVES: To attempt to identify the relationship of the key regulator molecules in paclitaxel-induced apoptosis using two metastatic cell lines: the human prostate carcinoma LNCaP line and the cervical carcinoma HeLa cell line. METHODS: Both LNCaP and HeLa cells were continuously exposed to clinically achievable concentrations of paclitaxel and observed for activation of programmed cell death as measured by cytotoxic dose-response curves, poly(adenosine diphosphate-ribose) polymerase cleavage, bcl-2 phosphorylation, and the activation of caspase-7 (interleukin-1 beta converting enzyme (ICE)-LAP3). RESULTS: Initially, we asked whether paclitaxel-induced bcl-2 phosphorylation is triggered by the spindle assembly checkpoint via an active cdc2 kinase-dependent pathway and whether phosphorylation of endogenous bcl-2 is the signal that activates cell death machinery. Paclitaxel-induced G2/M cell cycle arrest correlated with cdc2 kinase activity and bcl-2 phosphorylation. Olomoucin, a specific inhibitor of cyclin-dependent kinases, inhibited bcl-2 phosphorylation. On the basis of these studies, we then investigated whether bcl-2 was phosphorylated in a cell cycle-dependent fashion. Analysis of synchronized HeLa cells demonstrated that endogenous bcl-2 is phosphorylated in a G2/M cell cycle-dependent manner without apoptosis. CONCLUSIONS: Our results indicate that the events associated with paclitaxel-induced cytotoxicity are connected to each other and represent the signaling network of paclitaxel-induced mitotic arrest and cell death. In addition, we confirmed that the death-decision of paclitaxel-induced apoptosis is not mediated by bcl-2 phosphorylation and believe that this decision may be mediated by the activated spindle assembly checkpoint.

Rational use of chemotherapy. It is not just rat poison.

The role of chemotherapy in the management of advanced prostate cancer is expanding. Multiple regimens that use a variety of drugs have been developed. A chemotherapy regimen may appear to be a collection of randomly chosen agents. This article presents the theoretic foundation for the development of combination chemotherapy.

Oral chemotherapy for hormone refractory prostate cancer. The University of Michigan experience.

The use of oral chemotherapy for the treatment of malignant disease is expanding. The authors' experience with oral chemotherapy for hormone-refractory prostate cancer continues to grow. These therapies are well-tolerated and effective. Already, these regimens are being improved by hybridizing them with intravenous agents such as paclitaxel. Also, oral novel agents are being tested that may offer new options for the treatment of hormone-refractory prostate cancer.

Oral chemotherapy in the treatment of hormone-refractory prostate cancer.

Oral chemotherapy has become a major component of the treatment of advanced prostate cancer. The recognition that prostate cancer grows very slowly and must be treated continuously with active agents has led to the development of several therapeutic regimens. These regimens employ oral agents such as estramustine, cyclophosphamide, and etoposide, as they can be taken on a daily basis at home by the patients. These regimens have demonstrated activity in patients with hormone-refractory prostate cancer; declines in both prostate specific antigen and soft tissue lesions have been demonstrated.

The effect of hydrazine sulfate on prostate cancer growth.

Prostate cancer remains the most commonly diagnosed cancer in American males and is the second leading cause of cancer death in this group. Hydrazine sulfate, an inhibitor of gluconeogenesis, has been proposed as a means to improve nutritional status and improve survival in patients with solid tumors. We investigated the effects of hydrazine sulfate on both in vitro and in vivo models of prostate cancer. We examined the cytotoxicity of hydrazine sulfate in both human (LNCaP and PC-3) and animal (MAT-LyLu) prostate cancer cell lines. No growth inhibition was observed. In vivo, hydrazine sulfate did not suppress the growth of implanted Dunning rat prostate MAT-LyLu cells. Hydrazine sulfate does not have activity in these models of prostate cancer and may not be an appropriate therapy for patients with prostate cancer.

Carboplatin-induced cell death in model prostate cancer systems.

BACKGROUND: Many chemotherapeutic agents are believed to kill cancer cells by inflicting cellular damage which triggers the cell to enter apoptosis (programmed cell death). We investigated the means by which carboplatin induces cell death in three model cancer systems: the human prostate carcinoma cell lines PC-3 and LNCaP and the human cervical carcinoma cell line HeLa. MATERIALS AND METHODS: Drug cytotoxicity, cell cycle effects, bcl-2 deactivation, and multiple markers for apoptosis were utilized to examine carboplatin activity within these cell lines. RESULTS: In HeLa cells, carboplatin appears to induce an S-phase block followed by apoptosis. In contrast, PC-3 and LNCaP cells show no cell cycle phase block and die from necrosis rather than apoptosis. The effects of carboplatin contrast sharply with the effects of paclitaxel, which induces an M-phase block and apoptosis in all three cell lines. CONCLUSIONS: These results show that PC-3 and LNCaP cells are relatively resistant to carboplatin and suggest two causes of resistance: bypassing the cell cycle checkpoints which serve as points of entry into apoptosis, and incomplete execution of the effector mechanisms of apoptosis. Carboplatin resistance in the prostate cancer cell lines fits into the developing scheme of apoptosis-necrosis and raises valuable questions about the root causes of cancer resistance to chemotherapeutic agents.

Relationship of infant mortality to the availability of obstetrical care in Indiana.

BACKGROUND: Projects that are currently under way in Indiana to improve access to obstetrical care have not addressed the availability of these services in nonmetropolitan areas. This study was designed to identify all physicians who were providing obstetrical services in every county throughout the state to determine if there is a correlation between the availability of these services and the infant mortality rate in nonmetropolitan counties. METHODS: A state-wide physician profile maintained by the Indiana Academy of Family Physicians was cross-referenced with a telephone survey of all hospitals in the state to identify those physicians providing obstetrical services within each county in Indiana. The number of physicians in each county was then compared with the number of births per year by mothers from that county to determine whether nonmetropolitan counties had sufficient physicians to provide obstetrical services. Finally, these findings were compared with the most recent infant mortality rate for each nonmetropolitan county. RESULTS: A total of 610 family physicians, 311 obstetricians, and 75 general practitioners were providing obstetrical care in Indiana. There were 10 counties that did not have a physician who delivered babies practicing in that county. Thirty-two counties had more women who needed obstetrical care than the current number of physicians could serve. There was a negative correlation between physician availability and infant mortality in Indiana's nonmetropolitan counties (r = -.38; P less than .02). CONCLUSIONS: Access to care for pregnant patients is a major problem in rural Indiana and hampers Indiana's ability to reduce its current infant mortality rate.