Shaping future strategies for the pharmacological control of tumor cell metastases

Abstract

The eradication of established metastases in patients with malignant tumors is the single most important objective in clinical oncology. The current panel of antineoplastic agents discovered through random and semiempirical screening procedures has proven largely ineffective in treating disseminated disease and there is a clear and urgent need for more efficient antimetastatic drugs. Unfortunately, although progress has been made in examining the biology of metastatic spread, our understanding of the pharmacology, biochemistry and molecular genetics of this process is meager and insufficient to provide a rational foundation for the design of mechanism-based antineoplastic agents. Faced on the one hand with the failure of existing drugs to control metastatic spread and on the other with a dearth of alternative pharmacological approaches, the prospect of offering significantly improved therapy to the cancer patient of the 1990's is poor. The challenge of the coming decade lies in obtaining better insights into the molecular mechanisms of metastasis and using this information to identify pharmacological opportunities to curtail the proliferation of secondary tumor growths. As a first step toward this goal we need to define more rigorously what constitutes a therapeutic target in malignant disease and what steps in the pathogenesis of cancer metastasis represent the gravest risk to the patient and thus are most eligible for direct pharmacological intervention. In addressing these issues and developing future strategies for antimetastatic drugs, Paget's 100 year-old 'seed and soil' hypothesis continues to offer a useful conceptual framework for analysis of metastatic behavior. Although Paget's proposal has been validated by a century of clinical observation, efforts to define the 'seed and soil' theory in molecular terms have not been attempted. With the advent of more efficient methodologies for culturing human normal and neoplastic cells coupled with the availability of microanalytical technologies it now becomes possible to investigate and identify the complementary biochemical components of the tumor cell 'seed' and organ 'soil' that combine to encourage the proliferation of metastases. With this information the design of specific pharmacological strategies to uncouple the 'seed and soil' relationship may emerge as a potential therapeutic approach for antagonizing the growth of disseminated malignant tumors.

Antimetastatic action and toxicity on healthy tissues of Na[trans-RuCl4(DMSO)Im] in the mouse

“…Metastases represent the major obstacle to the achievement of cures after surgery and/or radiotherapy in that they often show low chemosensitivity to the available anticancer drugs [4][5][6]. The increase in knowledge of drugs which are selectively active against metastases (such as Na[trans-RuCl4(DMSO)Im]) may therefore contribute to the opening of the so-called 'window of selectivity' which is lacking in cancer chemotherapy.…”

What is known about melatonin, chemotherapy and altered gene expression in breast cancer

“…In Table II, a search was performed including as keywords melatonin (20,724 articles) melatonin and breast cancer (524 articles), and 28 drugs commonly used as chemotherapy in breast cancer treatment (6,9). Apart from tamoxifen (23 articles fulfilled the criteria ‘melatonin, breast cancer and tamoxifen’), the results show that there is limited information at the molecular level concerning the implication of co-treatment with the pineal indolamine and chemotherapy agents in breast cancer targeted therapy, and no report was available for 13 of the 28 drugs searched.…”

“…Chemotherapy compounds are usually applied by intravenous infusion and, through the bloodstream, they reach growing cancer cells in almost all body tissues. Chemotherapy compounds work by targeting cells with a high rate of self-renewal, which is a hallmark of cancer cells (6). Chemotherapy is recommended following surgery (adjuvant chemotherapy): Surgery is performed to dissect the tumor, and adjuvant therapy is administered to try to eliminate any cancer cells that had not been removed by the surgery and may spread out later (7).…”

Skeletal Muscle Phenotypically Converts and Selectively Inhibits Metastatic Cells in Mice

“…Understanding the cellular and molecular mechanisms leading to metastasis is of key importance for targeting metastatic cells since no efficient method to block metastasis exists [1], [2], [3], [4]. The metastatic conversion of a tumor cell involves cell-autonomous changes which alter cellular cross-talk in the tissue environment.…”