Polar solvents: a novel class of antineoplastic agents.

Abstract

It has been known for many decades that certain murine and human cancers can spontaneously mature to benign tissue. These observations have stimulated investigators to attempt to induce a state of more normal or benign differentiation in cancer cells using biologic substances or chemicals. Polar solvents including dimethylsulfoxide, dimethylformamide, and monomethylformamide have proven to be good inducers of maturational events in murine and human cancer cells. Moreover, several laboratories have demonstrated that polar solvents inhibit the growth of human tumor xenografts in nude mice. These findings have resulted in the entry of monomethylformamide into phase I clinical trials in America and Europe. Preclinical work further suggests that polar solvents may be useful agents in combination with conventional treatment modalities. The use of drugs such as monomethylformamide that can convert neoplastic cells to benign cells rather than kill the tumor cells represents an important conceptual departure from standard cytotoxic chemotherapy. The use of maturational-agent therapy should be considered as an important new development in the design of cancer treatment protocols.

Enhancement of the radiosensitivity of two human tumour cell lines by hexamethylene bisacetamide

“…There is a significant difference, however, between the sensitisation induced by these two polar compounds regarding the concentrations required: 2-3 mM of HMBA versus 170 mM of NMF. A difference in concentration of similar magnitude exists between NMF and HMBA with respect to the terminal differentiation of leukaemic cells and the non-terminal differentiation of solid tumour cells (Spremulli & Dexter, 1984;Reuben et al, 1976;Hughes et al, 1982). Our data, illustrating the HMBA-mediated radiosensitisation of clone A cells, however, are in contrast to the findings of Leith et al (1986).…”

“…Clone A cells, however, were more sensitive than EJ to the growth-inhibitory actions of HMBA. For both cell lines, the increase in culture doubling time was accompanied by a decrease in plating efficiency (Table I), a decrease in cell culture saturation density (data not shown) and changes in cell morphology, which are characteristic of the formation of a better differentiated phenotype (Spremulli & Dexter, 1984).…”

“…The treatment of many cell lines derived from solid tumours with the polar solvents, however, does not result in terminal differentiation, but merely the formation of a less malignant or better differentiated phenotype. This form of differentiation is characterised by an increase in cell culture doubling time, a decrease in clonigenicity, changes in cell morphology, a decrease in tumorigenicity when injected into nude mice and the production of specialised cell products associated with normal cells (Spremulli & Dexter, 1984). While anti-neoplastic benefits, such as a decrease in tumour aggressiveness, may be obtained from these types of cellular changes, upon withdrawal of the polar compounds, cells revert to their original malignant state.…”

“…The polar-solvent class of maturational agents can induce the terminal differentiation of a number of leukaemic cell lines in vitro (reviewed by Spremulli & Dexter, 1984). The treatment of many cell lines derived from solid tumours with the polar solvents, however, does not result in terminal differentiation, but merely the formation of a less malignant or better differentiated phenotype.…”

Heterogeneous response to differentiation induction with different polar compounds in a clonal rat rhabdomyosarcoma cell line (BA-HAN-1C)

“…Thus, in many cancers at least some of the tumour cells spontaneously exhibit abortive attempts at normal differentiation (Pierce, 1974). Furthermore, induction of differentiation has been successfully achieved in several in vitro systems (for review see Freshney, 1985) indicating that the malignant phenotype does not necessarily represent an irreversible state and that the conversion of malignant cells to a more benign phenotype through differentiation induction may become an alternative therapeutic approach (Metcalf, 1983;Spremulli & Dexter, 1984;Freshney, 1985;Sartorelli, 1985;Sachs, 1987). We recently described the effects of retinoic acid on the differentiation and proliferation of the clonal rat rhabdomyosarcoma cell line BA-HAN-IC (Gabbert et al, 1988a).…”