Negative selection and protection of normal progenitor cells for autografting

Abstract

Summary:Autologous bone marrow transplantation (ABMT) after high-dose chemotherapy is recognized as a curative approach to treating hematologic malignancies and some invasive solid tumors. However, tumor cells present in the bone marrow at the time of harvesting are a potential cause for relapse. Ex vivo marrow purging with very high doses of cytotoxic agents has been introduced in an attempt to remove neoplastic cells contaminating the autograft. The procedure, however, has been limited by its high toxicity to normal bone marrow progenitor cells. In their purging procedures, investigators have used agents such as amifostine, originally developed to protect against the effects of radiation and chemotherapy. In this article, the appropriateness of protecting normal cells with amifostine during various purging procedures will be reviewed. Keywords: autologous bone marrow transplantation; bone marrow purging; bone marrow progenitor cells; amifostine; cytoprotection; chemotherapy Maintenance of dose intensity is required for patients with cancer to benefit from the chemotherapeutic regimen. Escalation of the therapeutic dose is indicated primarily for consolidation therapy or alternatively when the disease is relapsing or is refractory to treatment. The cytotoxic burden, however, readily affects rapidly dividing normal cells. Consequently, hematopoietic bone marrow cells are primary targets, and progenitor stem cell depletion results. Hematologic toxicity is therefore a major complication of intensive chemotherapy or radiation therapy. Various means of protecting the bone marrow or accelerating its replenishment have been devised. Replacement of hematologic precursor cells through allogeneic bone marrow transplantation (alloBMT) after high-dose chemotherapy is a recognized curative approach for some malignancies. 1 However, the need for an HLA-matched donor, and treat- ment-related complications limit the usefulness of the procedure. Autologous bone marrow transplantation (ABMT) and peripheral blood stem cell (PBSC) reinfusion 2 have emerged as alternative approaches for the treatment of hematologic malignancies and selected tumors that respond to dose-escalation therapy. There is clear evidence of the clinical benefits of high-dose therapy with ABMT for the treatment of acute leukemias, 3-7 non-Hodgkin's lymphoma, [8][9][10][11] Hodgkin's disease, 10 multiple myeloma, 12 breast cancer, [13][14][15] and germ cell carcinoma of the testes. 16 Studies examining ABMT or PBSC reinfusion are also underway for patients with chronic myelogenous leukemia 17-19 and neuroblastoma. 20 Although treatment-related complications are less likely to arise with ABMT than with alloBMT, ABMT suffers from two drawbacks that may be responsible for the higher relapse rate seen with this procedure. The first results from the absence of graft-versus-host disease (GVHD). Attempts to eradicate GVHD have resulted in a high tumor relapse rate, indicating that a component of 'graft-versus-tumor' may be essential for eradicating malignant cells...

Radioprotection in mice following oral delivery of amifostine nanoparticles

“…In addition, clinical trials are also being conducted to evaluate the potential for adjunctive role of amifostine in chemoradiation therapy of cervical cancer (Small W Jr. 2003), and prostate cancer (Linares & Echols 2003;Menard et al 2003). In addition to being evaluated as a cytoprotector during chemo-and/or radio-therapy of several types of cancers, amifostine has been reported to be effective in reducing chemotherapy -induced progenitor cell toxicity during bone marrow transplantation (Cagnoni et al 1996;Douay 1998). Finally, two recent reviews (Andreassen et al 2003;Koukourakis 2002) provide a critical summary of the current and likely future role of amifostine as a cyto-or radio-protector.…”

SPPS of protected peptidyl aminoalkyl amides

“…On the other hand, several biologically active compounds contain in their structure linear or cyclic diamines. Examples of such compounds are the naturally occurring polyamines [3], the antipsychotic sulpiride 1 [4,5], and the wide range cytoprotectand amifostine 2 [6][7][8].…”

Φωτοδυναμική Θεραπεία Στην Κάθαρση Νεοπλασματικών Κυττάρων Από Το Μυελό Και Το Περιφερικό Αίμα Παιδιών Με Κακοήθειες

“…Επίσης, όπως ήδη αναφέρθηκε, είναι αδύνατον µε τις υπάρχουσες µεθόδους να διακριθούν ποιές από τις περιπτώσεις των υποτροπών οφείλονται σε υπολειπόµενη νόσο του ξενιστή και ποιες σε υπολειπόµενη νόσο του µοσχεύµατος. Η βιβλιογραφία σχετικά µε την κάθαρση του µυελού είναι τεράστια και ο ρόλος της έχει συζητηθεί εκτενώς σε πολλές ανασκοπήσεις [43][44][45][46][47][48][49]. Ένα τυπικό µόσχευµα µυελού περιέχει 10 10 -10 11 εµπύρηνα κύτταρα.…”