Sandra J. Meischen

Synergistic action of high-dose hydroxyurea when used with cyglophosphamide and certain new organoplatinum complexes in treatment of advanced L1210 leukemia

Seven new organoplatinum (Pt) compounds, cyclophosphamide (CY), and hydroxyurea (HU) were used singly and in combination in treatment of advanced L1210 leukemia in C57BL/6 × DBA/2 mice. In each experiment the Pt + CY combination was supra‐additive, as has been shown with other Pt compounds when used with CY. HU at the dose used (1000 mg/kg) was only minimally effective when used alone. However, six of the seven Pt + CY + HU combination regimens enhanced markedly the increased life span of treated mice when compared with the corresponding dual Pt + CY combination. The triple drug regimen yielded cure rates (>60‐day survival) up to 70% in individual experiments. Collectively, the cure rate was 11% with the various Pt + CY combinations, and was increased to 53% upon inclusion of HU in the regimen. It is suggested that HU may inhibit a process whereby potentially lethal DNA damage produced by Pt + CY would otherwise be repaired. A reduced efficacy of HU when used at a single, high‐dose level was also noted, and a possible mechanism and potential significance of this observation are discussed.

Potentiating Action of 5-Fluorouracil When Used in Combination with Platinum Compounds and Cyclophosphamide in Treatment of Advanced L1210 Leukemia

Nine new organoplatinum (Pt) compounds, cyclophosphamide (CY), and 5-fluorouracil (FU) were used singly and in combination in treatment of advanced L1210 leukemia in C57BL/6 X DBA/2 hybrid mice. In each experiment the Pt + CY dual combination was minimally supra-additive at the doses chosen. However, eight of the nine Pt + CY + FU combination regimens enhanced markedly the increased life span of treated mice as compared with the corresponding dual Pt + CY combination. Collectively, the cure rate (greater than 60-day survival) was less than 6% with the various Pt + CY combinations, and was increased to over 63% upon inclusion of FU in the regimens.

A comparison of methods for blocking staining of nucleic acids

Using rat spinal cord as test material 4 methods for blocking staining of nucleic acids with simple basic dyes have been compared. Two of these methods--a perchloric acid procedure for tissue blocks and a Ba(OH)2 technic for sections--block staining of RNA. The other two-immersion of sections in solutions of dichlorodiammine Pt II or in 10% zirconyl chloride-blocked staining of both RNA and DNA. None of these methods hydrolyze DNA sufficiently to produce a positive Feulgen and no loss of protein could be demonstrated. With the three metal containing procedures some metal could be demonstrated in the sections. This deposition was primarily in nucleic acid containing structures and was greatest and most widespread with the zirconyl chloride. The latter method altered the color of all hematoxylin technics to a deep red. The separation of nuclear stains on the basis of their bonding characteristics into three groups (Lillie et al. 1976) was confirmed.

Antitumor Action of Dichloro (4,5–dimethyl–o–phenylenediamine–N,N') platinum (II)

Summary Dichloro (4,5–dimethyl–o–phenyl–enediamine–N,N′)platinum (II) (DDPP) was synthesized by the reaction of 4,5–dimethyl–o–phenylenediamine with potassium tetrachlo–roplatinate. The resulting compound extended up to 176% the survival times of BALB/c mice bearing the Ehrlich ascites tumor and up to 74% the survival times of BDF1 mice bearing the L1210 leukemia. In studies using Ehrlich ascites tumor cells in vitro, DDPP was found to be a potent inhibitor of synthesis of DNA, RNA, and protein; the concentrations which conferred 50% inhibition following 1.5 hr of incubation with the compound were 3 × 10-5 to 5 × 10-5 M. Inhibition of nucleic acid and protein synthesis in vitro, once established, was not ameliorated by washing the cells with fresh medium devoid of DDPP. Cellular DNA, RNA, and protein, each appropriately labeled with a radioisotopically labeled precursor, became more acid–soluble upon incubation of the cells in vitro with DDPP. The rate of loss of viability of cells incubated in vitro with DDPP, as assessed by the trypan blue exclusion method, was found to be considerably greater than the rate obtained upon incubation of cells with an equivalent concentration of cis–dichlorodiammineplatinum(II).