Abstract
Most drugs available for cancer chemotherapy exert their effects through cytodestruction. Although significant advances have been attained with these cytotoxic agents in several malignant diseases, response is often accompanied by significant morbidity and many common malignant tumours respond poorly to existing cytotoxic therapy. Development of chemotherapeutic agents with non-cytodestructive actions appears desirable. Considerable evidence exists which indicates that (a) the malignant state is not irreversible and represents a disease of altered maturation, and (b) some experimental tumour systems can be induced by chemical agents to differentiate to mature end-stage cells with no proliferative potential. Thus, it is conceivable that therapeutic agents can be developed which convert cancer cells to benign forms. To study the phenomenon of blocked maturation, squamous carcinoma SqCC/Y1 cells were employed in culture. Using this system it was possible to demonstrate that physiological levels of retinoic acid and epidermal growth factor were capable of preventing the differentiation of these malignant keratinocytes into a mature tissue-like structure. The terminal differentiation caused by certain antineoplastic agents was investigated in HL-60 promyelocytic leukaemia cells to provide information on the mechanism by which chemotherapeutic agents induce cells to by-pass a maturation block. The anthracyclines aclacinomycin A and marcellomycin were potent inhibitors of N-glycosidically linked glycoprotein biosynthesis and transferrin receptor activity, and active inducers of maturation; temporal studies suggested that the biochemical effects were associated with the differentiation process. 6-Thioguanine produced cytotoxicity in parental cells by forming analog nucleotide. In hypoxanthine-guanine phosphoribosyltransferase negative HL-60 cells the 6-thiopurine initiated maturation; this action was due to the free base (and possibly the deoxyribonucleoside), a finding which separated termination of proliferation due to cytotoxicity from that caused by maturation.
Highlights
Exposure of HL-60 cells to pyrromycin or adriamycin, even at cytotoxic concentrations, did not result in a selective decrease in the synthesis of glycoproteins containing asparagine-linked oligosaccharides. These findings demonstrated a new biochemical site of action for aclacinomycin and marcellomycin and suggested that this activity was involved in the induction of the terminal differentiation of HL-60 leukaemia cells by these antitumour agents
Considerable additional fundamental information would appear to be required to most efficaciously apply the concepts of differentiation therapy to the treatment of malignant diseases of man. Phenomena such as commitment time, which often requires one to two cell generations of continuous exposure in culture to inducing agent to achieve an irreversible commitment to form endstage mature cells, suggests that continuous infusion of agents under test would be required for this period of time for optimum effects in patients with malignant disease
We have found that precommitment to memory initiated by a priming dose of one agent can be imparted to different inducing agents, making it possible to employ the clinical concept of spreading drug toxicity over several organ systems, while affecting the total neoplastic cell population
Summary
Significant advances have been made towards the cure and palliation of cancer with existing chemotherapeutic agents; since the mechanism of action of these drugs is dependent upon the cytodestruction of neoplastic cells, their beneficial effects are usually accompanied by significant morbidity. This suggests that approaches to cancer therapy should be sought that do not involve cell kill; one such approach envisions the conversion of malignant cells through induced differentiation to benign forms with no proliferative potential.
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