melphalan and Neoplasm-Regression--Spontaneous

The interest in TNF, discovered at the interface between inflammation and cancer, as an anti-cancer agent, has phased out in recent years. Indeed, despite its profound cytostatic and cytotoxic effects in primary tumors, the cytokine's systemic toxicity in general and its hepatotoxic and pro-metastatic nature in particular, prevent its routine use in cancer patients. An elegant approach to circumvent these problems consists in the local application of TNF in an isolated limb or organ setting, preferentially in the presence of cytostatic and alkylating agents, such as melphalan. However, this treatment, when locally applied during the perfusion of liver tumors, results in hepatotoxicity in a significant number of the patients, by means of a still unknown mechanism. The hemorrhagic necrosis of the tumors induced by TNF seems to be predominantly mediated by an induction of apoptosis as well as by an anti-angiogenic effect in the endothelial cells of the microvasculature supplying the tumor. These cells therefore represent a prime target for the action of anti-cancer drugs. In this review, we discuss preclinical studies which elucidated the mechanism of melphalan- and TNF-associated hepatotoxicity and, as a consequence, provided insights for preventing the adverse reactions of the drug. Moreover, we review recent findings aimed at improving the TNF molecule by means of specific mutations, or searching for alternative factors lacking the systemic toxicity of TNF.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Humans; Liver; Melphalan; Neoplasm Regression, Spontaneous; Neoplasms; Protein Conformation; Recombinant Proteins; Tumor Necrosis Factor-alpha

Topics: Adenocarcinoma; Animals; Antibodies, Neoplasm; B-Lymphocytes; Dose-Response Relationship, Immunologic; Female; Macrophages; Mammary Neoplasms, Experimental; Melphalan; Mice; Neoplasm Regression, Spontaneous; T-Lymphocytes

Topics: Animals; Antibody Specificity; Carcinoma 256, Walker; Haptens; Hindlimb; Immune Sera; Immunization, Passive; Immunotherapy; Melphalan; Neoplasm Regression, Spontaneous; Neoplasm Transplantation; Rats; Transplantation, Homologous

Studies of immunoglobulin synthesis, total body tumor cell number, and tumor kinetics were carried out in a series of patients with IgG multiple myeloma. The changes in tumor size associated with tumor growth or with regression were underestimated when the concentration of serum M-component was used as the sole index of tumor mass. Calculation of the total body M-component synthetic rate (corrected for concentration-dependent changes in IgG metabolism) and tumor cell number gave a more accurate and predictable estimate of changes in tumor size. Tumor growth and drug-induced tumor regression were found to follow Gompertzian kinetics, with progressive retardation of the rate of change of tumor size in both of these circumstances. This retardation effect, describable with a constant alpha, may be caused by a shift in the proportion of tumor cells in the proliferative cycle. Drug sensitivity of the tumor could be described quantitatively with a calculation of B(O), the tumor's initial sensitivity to a given drug regimen. Of particular clinical significance, the magnitude of a given patient's tumor regression could be predicted from the ratio of B(O) to alpha. Mathematical proof was obtained that the retardation constant determined during tumor regression also applied to the earlier period of tumor growth, and this constant was used to reconstruct the preclinical history of disease. In the average patient, fewer than 5 yr elapse from the initial tumor cell doubling to its clinical presentation with from 10(11) to more than 10(12) myeloma cells in the body. The reduction in total body tumor mass in most patients responding to therapy ranges from less than one to almost two orders of magnitude. Application of predictive kinetic analysis to the design of sequential drug regimens may lead to further improvement in the treatment of multiple myeloma and other tumors with similar growth characteristics.

Topics: Aged; Computers; Humans; Immunoglobulin G; Kinetics; Melphalan; Middle Aged; Models, Biological; Multiple Myeloma; Neoplasm Regression, Spontaneous; Prednisone

Topics: Antineoplastic Agents; Humans; Male; Melphalan; Neoplasm Regression, Spontaneous; Neoplasms; Research; USSR