Paul Calabresi

Use of growth factors in the elderly patient with cancer: a report from the Second International Society for Geriatric Oncology (SIOG) 2001 meeting

Over 70% of the total incidence of cancer recorded in Europe in 1996 was in the elderly population (> or =60 years). Despite such high statistics, elderly cancer patients have often been denied the treatment that younger patients routinely receive. The response of elderly cancer patients to full-dose chemotherapy treatment in several neoplasms is similar to that of younger patients, demonstrating that age should not be a barrier to the administration of potentially curative or palliative chemotherapy. In order to provide optimal treatment to elderly cancer patients, management guidelines are recommended which take into account various factors, such as the physical well-being of the patient, the type of malignancy and any conditions that may hamper compliance with chemotherapy. The evidence-based guidelines of the National Comprehensive Cancer Network (NCCN) in the US recommend that the safest and most effective treatment of cancer in older individuals may be achieved by proper patient selection based on comprehensive geriatric assessment, dose adjustment of renally excreted drugs, prophylactic use of haematopoietic growth factors in patients treated with chemotherapy of dose-intensity comparable to cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) and maintenance of haemoglobin levels > or =12 g/l. The objective of this article is to report the conclusions of the meeting of the International Society of Geriatric Oncology (SIOG) in September 2001, including the need for geriatric assessment to tailor the management of patients to their personal circumstances and general health and the importance of evidence-based guidelines for the management of elderly cancer patients cannot be over-estimated.

Amifostine cytotoxicity and induction of apoptosis in a human myelodysplastic cell line

Amifostine (AMF), a phosphorylated aminothiol, has been used to treat myelodysplastic syndrome (MDS), where it produces a stimulatory effect on hematopoiesis in bone marrow. To determine if AMF also produced a direct effect on human MDS cells, we planned a study to evaluate the effect of a continuous exposure to AMF on a human MDS cell line. AMF was shown to have a growth-inhibitory effect on MDS cells, with an IC(50) of 14 microM after a 5 day exposure. Cell cycle analysis revealed that a 5 day exposure to 20 microM AMF increased the percentage of cells in G0/G1 and this was accompanied by a decrease in the percentage of cells in S phase. Cytoflorometric and agarose-gel electrophoretic analysis revealed that this effect correlated with cell membrane alterations and DNA fragmentation consistent with an induction of apoptosis without affecting the expression of p53 protein or inducing any lymphoid or myeloid differentiation in the MDS cell line. We conclude that the continuous exposure of a human MDS cell line to AMF is cytotoxic and associated with an induction of apoptosis independent of alterations in p53 expression.

Recombinant interferon α2a synergistically enhances ganciclovir-mediated tumor cell killing in the herpes simplex virus thymidine kinase system

The herpes simplex virus thymidine kinase (HSV-TK) gene is being developed in the treatment of many different types of tumors. The HSV-TK gene sensitizes tumor cells to the antiviral drug ganciclovir (GCV) and mediates the bystander effect in which unmodified tumor cells are killed as well. Although this approach has shown a significant antitumor effect, the need to potentiate this therapy exists. The results of this study indicate that recombinant interferon α2a (IFNα2a) acts synergistically with GCV to kill HSV-TK-expressing PA1 human ovarian tumor cells. Furthermore, it enhances the bystander killing of nearby unmodified tumor cells that do not express the HSV-TK gene. Previous studies have suggested that in vitro and in vivo bystander effects may be mediated by different mechanisms. However, IFNα2a enhanced bystander killing in both systems, with the survival of mice bearing preexisting tumors being significantly prolonged when they were treated with IFNα2a and HSV-TK/GCV compared with either treatment alone. Mechanism studies have shown that treatment with IFNα2a and GCV caused an increase in cells in S phase 24 hours after therapy in the HSV-TK-expressing cells, but the mechanism of action of IFNα2a does not seem to be related to an increase in DNA damage, because GCV incorporation was not increased after treatment with IFNα2a. These findings suggest that IFNα2a may be a useful adjunctive therapy for the HSV-TK/GCV system.

Benzylacyclouridine Enhances 5-Fluorouracil Cytotoxicity against Human Prostate Cancer Cell Lines

At a nontoxic growth inhibitory concentration benzyloxyacyclouridine (BAU), a potent and specific inhibitor of uridine phosphorylase (UrdPase), enhanced 5-fluorouracil (5-FU) cytotoxic activity against human prostate cancer PC-3 and DU-145 cell lines. The BAU/5-FU combination exhibited greater antitumor activity in vivo using PC-3 human xenografts compared to 5-FU alone, with no associated increase in animal host toxicity. The mechanism(s) responsible for the enhanced in vitro and in vivo activity of this combination may involve enhanced formation of the 5-FU nucleotide metabolites FdUMP, FdUTP, and FUTP resulting in enhanced inhibition of thymidylate synthase (TS) and increased incorporation of fluoropyrimidine metabolites into tumoral RNA and DNA.