ABSTRACT
Using a murine model of melanoma we tested the effect of D-penicillamine administered in repetitive, daily injections, or as a single large dose injected either in saline or in a biodegradable polymer. We also studied the effect of a single intratumoral injection of benzyl-ester-D-penicillamine on the growth of the tumor. Daily injections of the drug or its administration in a polymer or benzyl-ester of D-penicillamine were all significantly inhibitory. The inhibitory effect manifested 4-5 days after injection. The inhibition lasted 8-10 days. There was no evidence of local or systemic toxicity and no changes in body weight. Several possible mechanisms for the inhibitory effect are presented.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Melanoma, Experimental/drug therapy , Penicillamine/analogs & derivatives , Animals , Antineoplastic Agents/adverse effects , Delayed-Action Preparations , Drug Administration Schedule , Esters , Female , Injections, Intralesional , Mice , Mice, Inbred C57BL , Penicillamine/administration & dosage , Penicillamine/adverse effects , Penicillamine/pharmacologyABSTRACT
Prevention of the formation of crosslinks and/or disintegration of already formed collagen fibrils in the tumor by known lathyrogens, beta-aminopropionitrile or D-penicillamine, may result in the weakening of tumor support, decreasing angiogenesis and promoting tumor regression. This paper reviews our studies with a single intratumoral injection of lipophilic lathyrogens and others, using a systemic administration to investigate the effect of both lathyrogens. Details of our experimental results are also given.
Subject(s)
Adenocarcinoma/drug therapy , Aminopropionitrile/therapeutic use , Antineoplastic Agents/therapeutic use , Mammary Neoplasms, Animal/drug therapy , Penicillamine/therapeutic use , Adenocarcinoma/blood supply , Adenocarcinoma/pathology , Aminopropionitrile/administration & dosage , Aminopropionitrile/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Esters/chemistry , Female , Fibrillar Collagens/metabolism , Injections, Intralesional , Mammary Neoplasms, Animal/blood supply , Mammary Neoplasms, Animal/pathology , Penicillamine/administration & dosage , Penicillamine/chemistry , RatsABSTRACT
This study extends the use of two lathyrogens, ss-aminopropionitrile (BAPN) and D-penicillamine (DPA) from daily systemic or local-topical administration to long-time acting agents. This was achieved by converting the hydrophilic drugs into lipophilic derivatives. The synthesis of functional derivatives of DPA consisted in esterification with methyl-, hexyl-, or benzyl alcohols in the presence of thionylchloride. The esters formed were hydrochlorides, acidic and soluble in water. During neutralization in vitro or in vivo by tissue fluid, an oily substance is formed that elutes from a hydrogel polymer at a much slower rate than hydroplilic DPA itself. The degree of lipophilicity, measured as a partition coefficient between octanol/water, was highest for hexyl ester and lowest for methyl ester DPA. A single injection of either DPA hexyl ester HCl or 3-hexyl(amino) propionitrile into the full thickness skin incision wound in rats significantly lowered the breaking strength of the wound 12 days after injection, indicating the interference with collagen cross-linking. Both agents injected into the breast adenocarcinoma in Fisher rats significantly inhibited tumor growth without any signs of local or systemic toxicity. We conclude that these lipophilic lathyrogens with prolonged effectiveness are suitable in the treatment of pathologies, consisting of excessively cross-linked or deposited collagen (fibrotic adhesions, strictures, stenosis, and scar contractures) and in the treatment of single, solitary tumors, malignant and benign.
