PubMed · 8415056
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B Friend. Trial after error.. https://pubmed.ncbi.nlm.nih.gov/8415056/
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It has been demonstrated that temperature-sensitive mutant p53 (val-->ala143) inhibits cell-proliferation at the permissive temperature, albeit to a lesser extent than wild-type p53 (Zhang et al.: EMBO J 13:2535-2544, 1994). We have studied its effect on the cell-cycle by dual-parameter flow cytometry, extended pulse-labeling, and pulse-chase experiments. p53ala143 interferes in Saos-2 cells at three levels with cell-cycle progression at permissive temperatures: it caused a G1-arrest, a reduced rate of DNA synthesis during S, and a prolonged G2/M. Strikingly, all these effects are transient. Continued culturing at 32 degrees C resulted in normal cell-cycle progression. Abrogation of the G1-block occurred even in the presence of high p21Waf1 protein levels, a negative cell-cycle regulator of which the expression is induced by wild-type p53.
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The rationale for and efficacy of bisphosphonates for pain due to cancer that has metastasized to bone are reviewed. Typical strategies for controlling metastatic bone pain have consisted of opioids, nonsteroidal anti-inflammatory drugs, surgery to stabilize bone, cancer chemotherapy, radiation therapy, and radiopharmaceuticals. Cancer metastasis to bone can produce pain through the release of prostaglandins, bradykinin, substance P, and histamine; growth of tumor into surrounding tissue; stretching of the periosteum; and pathological fractures. It has been suggested that bisphosphonates can benefit these patients by decreasing the amount of pain or decreasing analgesic requirements. Bisphosphonates bind to hydroxyapatite crystals, making it more difficult for osteoclasts to recognize exposed unmineralized bone surfaces, and are directly toxic to osteoclasts. Etidronate disodium, pamidronate disodium, clodronate disodium, and alendronate sodium are bisphosphonates that have been studied in patients with painful bone metastases. Although each of these has shown at least some benefit, the most promising agent appears to be pamidronate, especially the i.v. formulation given monthly. Although oral formulations of this agent have been studied, poor bioavailability and adverse effects limit their usefulness. Adverse effects of bisphosphonates include GI reactions, impairment of renal function, anemia, and electrolyte abnormalities. Bisphosphonates are of some benefit in relieving metastatic bone pain, but the exact role, agent, route, and duration are issues that need further study.