Reduced glutathione protects against cisplatin-induced neurotoxicity in rats.

Reduced glutathione (GSH) is reported to diminish cisplatin-induced neurotoxicity, and it was for this reason that we studied GSH in an animal model of cisplatin neuropathy. The neuropathy was evaluated by measuring the sensory nerve conduction velocity (SNCV) in young adult Wistar rats. GSH injections (i.v.) were given twice weekly, within five minutes before cisplatin was injected (i.p.). In a first experiment GSH (500 mg/kg) in combination with a low-dose cisplatin treatment (1 mg/kg, 10 weeks) was investigated. Animals treated with cisplatin and placebo developed a neuropathy (SNCV at week 10: age controls, 61.9 m/s; cisplatin alone, 44.2 m/s), whereas rats treated with cisplatin and GSH did not (SNCV, 61.9 m/s). The same dose of GSH was used in combination with a high-dose cisplatin schedule (2 mg/kg, 5 weeks' treatment plus 5 weeks' recovery). Again, GSH protected animals against the development of neuropathy (SNCV at week 10: age controls, 61.9 m/s; cisplatin alone, 50.6 m/s; cisplatin plus GSH, 61.1 m/s). In another experiment four lower doses of GSH (25, 50, 100, and 200 mg/kg) were tested in combination with the low-dose cisplatin protocol (1 mg/kg, 11 weeks). The cisplatin group developed a neuropathy (SNCV at week 11: cisplatin alone, 50.2 m/s; age controls, 60.6 m/s). Only the dose of 200 mg GSH/kg was found to protect against the development of a neuropathy (SNCV, 61.0 m/s). In an antitumor study GSH administered at 300 mg/kg in combination with cisplatin at 1.5 mg/kg did not diminish the curative effect of cisplatin. We conclude that GSH prevents cisplatin-induced neuropathy and that it should be investigated further in the clinic.

The antineoplastic activity of 4'-deoxydoxorubicin in murine solid tumors.

The antineoplastic effectiveness of 4'-Deoxydoxorubicin (DeDXR), a novel anthracycline with reduced cardiotoxicity, has been compared with that of Doxorubicin (DXR) in a panel of murine solid tumors of different histo-type, growth rate, and metastatic behaviour. Using doses of comparable toxicity and optimal treatment schedules, DeDXR was more active in the RC2 renal carcinoma, mFS6 fibrosarcoma, and Madison 109 carcinoma models, as judged by effects on primary and secondary tumor growth inhibition, increase in survival and/or proportion of tumor-free animals. In the M5076 reticulosarcoma DeDXR was equally effective with DXR, whereas the latter was more active on the PRSCT-5 prostate tumor.

Activity and distribution of iv and oral 4-demethoxydaunorubicin in murine experimental tumors.

The antitumor activity of 4-demethoxydaunorubicin ( 4DDM ) compared to its parent compound daunorubicin (DM) was investigated in C57BL/6 mice bearing a T-cell lymphoma, the EL-4, chosen because of its sensitivity to this compound. 4DDM was moderately effective against Lewis lung carcinoma and M5076 ovarian reticulosarcoma tumor systems. Against the EL-4 tumor, after either iv or oral treatment, 4DDM had a good therapeutic effect (survival time in treated mice was almost double that in untreated mice) which was comparable to that of iv doxorubicin. Serum and tissue distribution of 4DDM and its reduced metabolite 4- demethoxydaunorubicinol , given either iv or orally at therapeutic doses to EL-4-bearing mice, was then compared with iv DM using a high-performance liquid chromatography technique with fluorimetric detection. DM seemed to be cleared faster and to a greater extent by metabolism than 4DDM , with half-lives after iv treatment of 23 hrs for 4DDM versus 4.6 hrs for DM. The reduced metabolite in serum amounted to greater than 100% of the concentration of the native compound for DM and less than 20% for 4DDM . By both the iv and oral routes, 4DDM appeared to be concentrated and retained in tissues to a proportionally higher extent than DM, with drug exposure being at least twice as high with correspondingly longer half-lives in almost all tissues investigated, including the tumor. Moreover, this demethoxy analog appeared to be somewhat more selective than DM, since the relative capacity of the tumor tissue to accumulate this compound seemed higher than that of other organs (eg, heart and spleen) reported to be targets of toxicity. Oral administration gave more favorable distribution, resulting in the highest tumor to heart and spleen concentration ratio; this suggests a superiority of this route of administration.

Effects of disodium etidronate in murine tumor models.

This study was designed to elucidate the effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) in experimental rodent tumors. EHDP had no antitumor activity against the L1210 leukemia implanted i.p. and against sarcoma 180, Lewis lung carcinoma (3LL) and Walker 256/B carcinoma injected i.p., s.c. or i.m. respectively. EHDP did not interfere with the antitumor activity of commonly used conventional chemotherapeutic agents (adriamycin, cyclophosphamide, 5-fluorouracil, bis-chloroethylnitrosourea) in the L1210 and 3LL models. EHDP reduced proportionally to the dose the hypercalcemia and hypercalciuria due to the Walker 256/B carcinoma growth. In an effort to evaluate whether EHDP-treated osseous tissues were more refractory to tumor growth, cells from sarcoma 180 and 3LL carcinoma were implanted intratibially (i.t.). Growth of 3LL cells was not consistently affected by EHDP, whereas a modest, but significant, growth inhibition was consistently observed with sarcoma 180 injected i.t. Growth of sarcoma 180 implanted i.p. or s.c. was not reduced by this drug, thus suggesting that inhibition of i.t. sarcoma 180 was in fact related to alterations of osseous tissues by EHDP. Inoculation of Walker 256/B carcinoma intra-aortically resulted in osteolytic bone lesions in the hind limbs. EHDP inhibited the formation of bone metastasis under these conditions.

The antineoplastic activity of hexaziridinocyclotriphosphazene (Myko 63) in murine tumors.

The antineoplastic activity of hexaziridinocyclotriphosphazene (Myko 63) has been investigated in a panel of murine ascitic and solid tumors. Myko 63 was found to significantly retard primary and secondary tumor growth and to prolong the survival rates in each of the nine models employed. These included the L1210 and P388 leukemias, P815 mastocytoma, the 3LL and Madison 109 carcinomas, M5076 reticulum cell sarcoma, the line 26 colon and line 16 mammary carcinomas, and an intracranially implanted ependymoblastoma. The possible modes of action of this compound and the potentials of cyclophosphazenes, a chemical class largely unexplored as antitumor agents are discussed.

The immunomodulatory activity of the plant proteins Momordica charantia inhibitor and pokeweed antiviral protein.

The immunological activity of Momordica Charantia inhibitor (MCI) and of Pokeweed antiviral protein (PAP-S), 30,000 daltons plant proteins possessing close similarity to Ricin A chain as inhibitor of protein synthesis, was investigated in mice. In vivo, single nontoxic injections of microgram amount of these substances delayed H2-incompatible skin allograft rejection, splenocyte responsiveness to ConA and PHA, but not to LPS, and abrogated the PFC response to a T-dependent (SRBC) antigen while totally sparing that to a T-independent (S III) stimulus. Injection of these substances could also reduce NK cell activity while increasing macrophage-mediated spontaneous cytotoxicity. In vitro, MCI and PAP-S at non-cytotoxic concentrations inhibited lymphoid cell responsiveness to PHA and ConA, but not to LPS, and markedly enhanced macrophage-dependent cytotoxicity.