Treatment of tumours with the combination of WR-2721 and cis-dichlorodiammineplatinum (II) or cyclophosphamide

Abstract

Summary.-The ability of WR-2721 [S-2(3-aminopropylamino)ethyl-phosphorothioic acid] to selectively protect the host against the toxic effects of multiple doses of cis-dichlorodiammineplatinum [cis-Pt] or cyclophosphamidej [CY] has been studied in mice and rats bearing 3 different tumours. Selective protection against cis-Pt induced nephrotoxicity has been demonstrated under all conditions studied, with the extent of protection being inversely related to the size of the cis-Pt dose. For example, pre -treatment with 200 mg/kg of WR-2721 30 min before each weekly dose of 2 mg/kg of cis-Pt allows the administration of this cytotoxic agent for 3 times longer before nephrotoxic injury. In none of these studies was there tumour protection. The same pattern was observed with CY, but quantitation of the extent of marrow protection was not possible for the multiple treatment studies, due to the longer latent period between induced and observed death with this drug. We conclude, therefore, that for both of these drugs, selective protection of the kidney and marrow is not only maintained under conditions of multiple treatment, but actually enhanced due to the need for smaller doses of cytotoxic agents in these protocols.

Modification by WR 2721 of the response to chemotherapy of tumours and normal tissues in the mouse

“…In most radiation studies a time of 15-30min has been chosen as this allows peak levels of drug to be attained in most normal tissues whilst allowing little time for the slower absorption into tumours (Yuhas, 1980b). A similar rationale has been used in chemoprotection experiments (Yuhas, 1979;Yuhas & Culo, 1980;Yuhas et al, 1980;Twentyman, 1981). A potential artefact of drug interaction in the bloodstream has, however, been pointed out when very short times (5-15min for nitrogen mustard) are used (Yuhas, 1979).…”

“…Reports of protection of normal tissues against nitrogen mustard (Yuhas, 1979), cis-P (Yuhas & Culo, 1980) and CTX were all accompanied by findings of a lack of protection of tumours. Using the bone marrow CFUs assay in LAF1 mice, Wasserman et al, (1981) examined the ability of WR 2721 to protect against nitrogen mustard, CTX, BCNU, cis-P and 5-fluorouracil and obtained protection factors in the range 1.5 to 4.6.…”

“…More recently a number of papers have appeared which indicate that this compound is also able to selectively protect normal tissues in the mouse or rat against a number of cytotoxic drugs whilst having little or no effect upon the anti-tumour efficacy of these agents (Yuhas, 1979;Yuhas & Culo, 1980;Yuhas et al, 1980;Wasserman et al, 1981). In our own study of cyclophosphamide (CTX) in combination with WR 2721, however, we found significant protection of two mouse tumours against CTX, whilst seeing less protection of normal tissues than reported by others (Twentyman, 1981).…”

Prophylaxis of kanamycin-induced ototoxicity by a radioprotectant

“…Another factor influencing the protective properties of WR 2721 is its tissue distribution. WR 2721 does not appreciably penetrate tumors [23,35,38] nor does it cross the bloodbrain barrier [41].…”

“…It was simultaneously reported that these same thiols also protected against nephrotoxicity due to antineoplastic alkylating agents [41,3,6,14,5,7,10,27,39], e.g., nitrogen mustards, phenylalanine mustard (L-PAM), sarcolysine, busulfan, cyclophosphamide and cisplatinum. Pretreatment with WR 2721 has recently been shown to offer nephroprotection against HNs, L-PAM, cyclophosphamide and cisplatinum [41,39,37].…”