Three-drug combination of MKC-442, lamivudine and zidovudine in vitro: potential approach towards effective chemotherapy against HIV-1.
OBJECTIVE
MKC-442 (6-benzyl-1-ethoxymethyl-5-isopropyluracil), a potent non-nucleoside reverse transcriptase inhibitor, is a promising candidate for the treatment of HIV-1 infection and is now undergoing clinical trials. We studied the in vitro activity of MKC-442 against HIV-1 replication in a three-drug combination regimen with zidovudine (ZDV) and lamivudine (3TC).


METHODS
Drug-drug interactions in MT-4 cells and peripheral blood mononuclear cells (PBMC) infected with HIV-1IIIB were evaluated. The multiple drug effect analysis based on the median effect principle was applied, and the combination indices were calculated using a computer software program. The occurrence of viral breakthrough was investigated during a long-term culture of HIV-1-infected MT-4 cells.


RESULTS
When MKC-442 was combined with 3TC and ZDV, they synergistically suppressed HIV-1 replication in MT-4 cells over a wide range of doses irrespective of the endpoints for synergy calculations. Similar results were also obtained in PBMC. An arbitrary combination ratio of 10:100:1 for MKC-442:3TC:ZDV showed stronger synergism than any other ratios examined. As a result of synergy in the three-drug combination, the dose of each drug could be reduced by four- to 24-fold. The three-drug combination markedly delayed or even completely suppressed HIV-1 replication at least for 40 days. Virus emerged in the presence of three drugs at lower doses, although it did not contain any amino-acid mutations in the sequenced reverse transcriptase region and did retain full sensitivity to all three drugs.


CONCLUSIONS
Our results demonstrate a potential efficacy of MKC-442 in combination with 3TC and ZDV, and the three-drug combination should be considered for treatment of AIDS patients.
Piras
G
G
Division of Human Retroviruses, Faculty of Medicine, Kagoshima University, Japan.
Nakade
K
K
Yuasa
S
S
Baba
M
M
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase / Q000187:drug effects / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology*
D019380:Anti-HIV Agents; D019259:Lamivudine; D015215:Zidovudine; D014498:Uracil; D054303:HIV Reverse Transcriptase; C083858:emivirine